Calycosin alleviates cerebral ischemia/reperfusion injury by repressing autophagy via STAT3/FOXO3a signaling pathway.
As a common cerebrovascular disease (CVD) of the elderly, ischemic stroke (IS) is characterized by high disability and mortality. Excessive autophagy induced by IS is implicated in neuronal death, therefore, the inhibition of immoderate autophagy is viewed as a potential therapeutic avenue to treat IS. Calysoin (CA) is a bioactive component of Radix Astragali, which has been widely used to treat CVDs. However, the mechanism of the treatment of IS by CA is still problematic. Based on the result of network pharmacology, whether CA inhibited autophagy by regulating the STAT3/FOXO3a pathway to alleviate cerebral ischemia-reperfusion injury (CIRI) was investigated in vivo and in vitro for the first time. Integrate computational prediction and experimental validation based on network pharmacology. In current study, network pharmacology was applied to predict the mechanism of the treatment of IS by CA, and it was shown that CA alleviated CIRI by inhibiting autophagy via STAT3/FOXO3a signaling pathway. One hundred and twenty adult male specific pathogen-free Sprague-Dawley rats in vivo and PC12 cells in vitro were used to verify the above prediction results. The rat middle cerebral artery occlusion/reperfusion (MCAO/R) model was established by suture method, and oxygen glucose deprivation/re-oxygenation (OGD/R) model was used to simulate cerebral ischemia in vivo. The content of MDA, TNF-α, ROS and TGF-β1 in rat serum were detected by ELISA kits. The mRNA and protein expressions in brain tissue were detected by RT-PCR and Western Blotting. The expressions of LC3 in brain were detected immunofluorescent staining. The experimental results demonstrated that administration of CA dosage-dependently improved rat CIRI as evidenced by the reduction in the cerebral infarct volume, amelioration of the neurological deficits. HE staining and transmission electron microscopy results revealed that CA ameliorated cerebral histopathological damage, abnormal mitochondrial morphology, and damaged mitochondrial cristae structure in MCAO/R rats. CA treatment exerted protective effects in CIRI by inhibiting inflammation response, oxidative stress injury, and cell apoptosis in rat and PC12 cells. CA relieved excessive autophagy induced by MCAO/R or OGD/R through downregulating the LC3Ⅱ/LC3Ⅰ ratio and upregulating the SQSTM1 expression. CA treatment also decreased p-STAT3/STAT3 and p-FOXO3a/FOXO3a ratio in the cytoplasm and modulated the autophagy-related gene expression both in vivo and in vitro. Treatment with CA attenuated CIRI by reducing excessive autophagy via STAT3/FOXO3a signal pathway in rat and PC12 cells.


Identification of Ribonuclease 6 as an immunoinflammatory key gene associated with the glomerular injury in diabetic nephropathy.
Diabetic nephropathy is one of the major causes of end-stage renal disease, and the pathogenesis of the disease has not been elucidated. While the immunoinflammatory response plays an essential role in the progression of diabetic nephropathy. Glomerular expression dataset in diabetic nephropathy was obtained from the GEO database. Differentially expressed genes were identified and functional enrichment analysis was performed to find genes associated with immunity and inflammation from them. The hub genes of immunoinflammatory were identified using MCODE after establishing the PPI network and gene expression was verified with diabetic nephropathy model rats. Xcell was used to assign immune cells to diabetic nephropathy glomerular samples to detect significant changes in immune cells and to analyze correlations with the hub gene. We found 120 DEGs associated with immunity and inflammation, Ribonuclease 6 was the Hub gene with the highest MCODE score. Xcell analysis revealed significant changes of immune cells in DN glomeruli, including upregulated Activated DCs, Conventional DCs, CD4+ Tem, Epithelial cells, Macrophages, Macrophages M1, and Memory B-cells. RNase6 expression showed the highest positive correlation with Macrophages M1, Activated DCs, and Conventional DCs. We verified through the Nephroseq v5 database that RNase6 expression was elevated in DN glomeruli and negatively correlated with glomerular filtration rate. Animal studies revealed that the kidney of DN model rats showed increased RNase6 expression together with inflammatory factor TNF-alpha and chemokine MCP-1. Our study identified RNase6 as a diagnostic and prognostic biomarker for diabetic nephropathy and found that it may play an essential role in the immunoinflammatory damage to the glomerulus.


[Illogical association nalmefene and opioids: Analysis in the French pharmacovigilance database].
Nalmefene, an opioid antagonist, causes withdrawal syndromes in patients exposed to an opioid agonist. Despite its contraindication, this illogical drug association persists, especially with opioid substitution drugs (ODS). We measured the benefits of the modification in the summary of product characteristics (SPC) in March 2015 and the package leaflet of Selincro® in September 2016 on this misuse. We analyzed the observations regarding a use of nalmefene with an opioid between September 2014 and August 2017 in the French pharmacovigilance database and the laboratory. The combination nalmefene and methadone was reported in about half of the cases (46/90). Observations were highest between October 2015 and March 2016 (29/90) and then decreased. Those with self-medication have increased. From October 2016, declarations become rarer. The effect of modifications in the SPC and the package leaflet on the use of nalmefene with ODS was real and progressive.


Spontaneous coronary artery dissection--a case report and review of the literature.
Spontaneous coronary artery dissection remains an extremely rare cause of myocardial ischemia and infarction. The clinical picture of spontaneous coronary dissection is often sudden cardiac death or fatal myocardial infarction. This report describes a previously healthy woman who developed spontaneous coronary artery dissection. She presented with sudden onset of chest pain and was found to have evidence of acute inferior wall myocardial infarction. She received streptokinase immediately after admission to the coronary care unit. Coronary angiographic studies revealed a linear dissection involving the proximal and mid segments of the right coronary artery.


Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: a novel consideration in atrial remodeling.
Atrial fibrillation (AF) causes tachycardia-induced atrial electrical remodeling, contributing to the progressive nature of the arrhythmia. Ventricular dysfunction due to a rapid response to AF can cause structural remodeling, but whether AF itself directly promotes atrial fibrosis is controversial. This study investigated the hypothesis that rapid atrial cardiomyocyte activation produces factors that influence atrial fibroblast proliferation and secretory functions. Cultured canine atrial fibroblasts were treated with medium from rapidly-paced atrial cardiomyocytes, non-paced cardiomyocytes and cardiomyocyte-pacing medium only, and analyzed by [(3)H]thymidine incorporation, Western blot and real-time RT-PCR. Rapidly-paced cardiomyocyte-conditioned medium reduced [(3)H]thymidine uptake compared to non-paced cardiomyocyte-conditioned medium and medium alone (approximately 85%, P<0.01). Rapidly-paced cardiomyocyte medium increased alpha SMA protein (approximately 55%, p<0.001), collagen-1 (approximately 85%, P<0.05) and fibronectin-1 (approximately 205%, P<0.05) mRNA expression vs. controls. The angiotensin-1 receptor blocker valsartan attenuated pacing-induced alpha SMA changes but did not affect fibroblast proliferation. Suppression of contraction with blebbistatin did not prevent tachypacing-induced changes in [(3)H]thymidine uptake or alpha SMA upregulation, pointing to a primary role of electrical over mechanical cardiomyocyte activity. Atrial tissue from 1-week atrial-tachypaced dogs with ventricular rate control similarly showed upregulation of alpha SMA protein (approximately 40%, P<0.05), collagen-1 (approximately 380%, P<0.01) and fibronectin-1 (approximately 430%, P<0.001) mRNA versus shams. Rapidly-paced cardiomyocytes release substances that profoundly alter cardiac fibroblast function, inducing an activated myofibroblast phenotype that is reflected by increased ECM-gene expression in vivo. These findings are consistent with recent observations that AF per se may cause ECM remodeling, and have potentially important consequences for understanding and preventing the mechanisms underlying AF progression.


Corticosteroid therapy in patients with primary viral pneumonia due to pandemic (H1N1) 2009 influenza.
During the first pandemic, some patients with pandemic (H1N1) 2009 influenza were treated with corticosteroids. The objective of this study was to assess the effect on survival of corticosteroid therapy in patients with pandemic (H1N1) 2009 influenza. Prospective, observational, multicenter study performed in 148 ICU. Data were recorded in the GTEI/SEMICYUC registry. Adult patients with pandemic (H1N1) 2009 influenza confirmed by rt-PCR were included in the analysis. Database records specified corticosteroid type and reason for corticosteroid treatment. 372 patients with the diagnosis of primary viral pneumonia and completed outcomes treated in an ICU were included in the database. Mechanical ventilation was used in 70.2% of the patients. 136 (36.6%) patients received corticosteroids after a diagnosis of primary viral pneumonia. Obesity (35.6% vs 47.8% p = 0.021) and asthma (7.6% vs 15.4% p = 0.018), were more frequent in the group treated with corticosteroids. A Cox regression analysis adjusted for severity and potential confounding factors found that the use of corticosteroid therapy was not significantly associated with mortality (HR = 1.06, 95% CI 0.626-1.801; p = 0.825). Corticosteroid therapy in a selected group of patients with primary viral pneumonia due to pandemic (H1N1) 2009 influenza does not improve survival.


Multicolor Fluorescence In Situ Hybridization (FISH) Approaches for Simultaneous Analysis of the Entire Human Genome.
Analysis of the organization of the human genome is vital for understanding genetic diversity, human evolution, and disease pathogenesis. A number of approaches, such as multicolor fluorescence in situ hybridization (FISH) assays, cytogenomic microarray (CMA), and next-generation sequencing (NGS) technologies, are available for simultaneous analysis of the entire human genome. Multicolor FISH-based spectral karyotyping (SKY), multiplex FISH (M-FISH), and Rx-FISH may provide rapid identification of interchromosomal and intrachromosomal rearrangements as well as the origin of unidentified extrachromosomal elements. Recent advances in molecular cytogenetics have made it possible to efficiently examine the entire human genome in a single experiment at much higher resolution and specificity using CMA and NGS technologies. Here, we present an overview of the approaches available for genome-wide analyses. © 2018 by John Wiley & Sons, Inc.


Invertebrate humoral factors: cytokines as mediators of cell survival.
The presence and the different functional aspects of cytokine-related molecules in invertebrates are described. Cytokine-like factors affect immune functions, such as cell motility, chemotaxis, phagocytosis and cytotoxicity. In particular, cell migration shows a species-specific effect for IL-1alpha and TNF-alpha and a dose-correlated effect for IL-8, PDGF-AB and TGF-beta1. Apart from some exceptions, the phagocytic effect increases significantly at all the concentrations tested and with all the species used. PDGF-AB, TGF-beta1 and IL-8 provoke conformational changes in mollusk immunocytes, involving the signaling transduction pathways of phosphatidylinositol and cAMP. PDGF-AB and TGF-beta1 partially inhibit the induced programmed cell death in an insect cell line, and the survival effect is mediated by the activation of phosphatidylinositol 3-kinase, PKA and PKC. The exogenous administration of these growth factors in an invertebrate wound repair model showed that they are able to control the wound environment and promote the repair process by accelerating the coordinated activities involved. Moreover, IL-1alpha, IL-2 and TNF-alpha are able to induce nitric oxide synthase. PDGF-AB and TGF-beta1 provoke an increase in neutral endopeptidase-24.11 (NEP)-like activity in membrane preparations from mollusk immunocytes, while NEP deactivates the PDGF-AB- and TGF-beta1-induced cell shape changes. Cytokines are also involved in invertebrate stress response in a manner extremely similar to that in vertebrates. Several studies suggest the existence on the mollusk immunocyte membrane of an ancestral receptor capable of binding both IL-2 and CRH. Furthermore, the competition found between CRH and a large number of cytokines supports the idea that invertebrate cytokine receptors show a certain degree of promiscuity. The multiple functions of cytokines detected in invertebrates underline another characteristic of mammalian cytokines, i.e. their great pleiotropicity. Altogether, the studies on the function of the invertebrate humoral factors show a close overlapping with those found in vertebrates, and the hypothesized missing correlation between invertebrate and vertebrate cytokine genes that is emerging from the limited molecular biology data present in literature might represent a very peculiar strategy followed by Nature in the evolution of cytokines.


Microcalcifications increase coronary vulnerable plaque rupture potential: a patient-based micro-CT fluid-structure interaction study.
Asymptomatic vulnerable plaques (VP) in coronary arteries accounts for significant level of morbidity. Their main risk is associated with their rupture which may prompt fatal heart attacks and strokes. The role of microcalcifications (micro-Ca), embedded in the VP fibrous cap, in the plaque rupture mechanics has been recently established. However, their diminutive size offers a major challenge for studying the VP rupture biomechanics on a patient specific basis. In this study, a highly detailed model was reconstructed from a post-mortem coronary specimen of a patient with observed VP, using high resolution micro-CT which captured the microcalcifications embedded in the fibrous cap. Fluid-structure interaction (FSI) simulations were conducted in the reconstructed model to examine the combined effects of micro-Ca, flow phase lag and plaque material properties on plaque burden and vulnerability. This dynamic fibrous cap stress mapping elucidates the contribution of micro-Ca and flow phase lag VP vulnerability independently. Micro-Ca embedded in the fibrous cap produced increased stresses predicted by previously published analytical model, and corroborated our previous studies. The 'micro-CT to FSI' methodology may offer better diagnostic tools for clinicians, while reducing morbidity and mortality rates for patients with vulnerable plaques and ameliorating the ensuing healthcare costs.


Sensorimotor enhancement in mouse mutants lacking the Purkinje cell-specific Gi/o modulator, Pcp2(L7).
Pcp2(L7) is a GoLoco domain protein specifically and abundantly expressed in cerebellar Purkinje cells. It has been hypothesized to "tune" G(i/o)-coupled receptor modulation of physiological effectors, including the P-type Ca(2+) channel. We have analyzed a mouse mutant in which the Pcp2(L7) gene was inactivated and find significant anatomical, behavioral and electrophysiological changes. Anatomically, we observed mild cerebellar hypoplasia. Behaviorally, the mutants were altered in modalities atypical for a traditional cerebellar mutant, and oddly, all of these changes could be considered functional enhancements. This includes increased asymptotic performance in gross motor learning, increased rate of acquisition in tone-conditioned fear, and enhanced pre-pulse inhibition of the acoustic startle response. Electrophysiological analysis of Purkinje cells in the mutants reveals depression of the complex spike waveform that may underlie the behavioral changes. Based on these observations we suggest that the Pcp2(L7) protein acts as a sensorimotor damper that modulates time- and sense-dependent changes in motor responses.


Investigation on signal transduction pathways after H(1) receptor activated by histamine in C6 glioma cells: involvement of phosphatidylinositol and arachidonic acid metabolisms.
Information related to histamine-induced cellular responses in C6 glioma cells through second messenger pathways has not been fully studied, especially the involvement of arachidonic acid (AA) metabolism. In addition, specific labeled ligand binding to histamine receptor sites still needs to be clarified. Labeled mepyramine ligand was used to study its binding sites; [(3)H] inositol was used to detect inositol 4-phosphate (IP(1)) formation, and fura-2/AM was used to detect intracellular free calcium ion ([Ca(2+)]i) level activated by the phosphatidylinositol-phospholipase C (PI-PLC) pathway. Also, labeled AA was used to detect the metabolism of AA and its metabolites release via the activation of phospholipase A2 in the presence of histamine. C6 glioma cells incubated with histamine in the presence of 10 mM LiCl for 60 minutes induced an increase of IP(1) and glycerophosphoric-inositol (GPI) accumulation. In addition, histamine caused an increase of extracellular AA with its metabolite release, eliciting a transient and sustained increase of free [Ca(2+)]i. The sustained increase of [Ca(2+)]i was almost or completely blocked by La(3+) and excess ethylene diamine tetraacetic acid. The calcium ion influx associated with the sustained phase required the presence of histamine on the receptor sites, and could be blocked by a H(1) antagonist, chlorpheniramine. C6 glioma cells possess histamine H(1) receptors that have affinity towards [(3)H]mepyramine binding, and are coupled to PI-PLC to generate inositol phosphates and to increase [Ca(2+)]i, and they are coupled to phospholipase A2 (PLA2) to generate GPI and AA with its metabolite release. The transient increase in [Ca(2+)]i can be attributed to Ca(2+) release from intracellular stores, whereas the sustained increase in [Ca(2+)]i is due to influx of extracellular calcium ions. The sustained increase in [Ca(2+)]i plays a role in the activation of histamine receptor-coupled PLA2.


Amphiphilic and hydrophilic forms of acetylcholinesterase from sheep platelets.
Acetylcholinesterase (AChE, EC 184.108.40.206) was extracted from sheep platelets by successive homogenizations, yielding low-salt soluble (LSS), high-salt soluble (HSS) and detergent-soluble (DS) fractions. These accounted, respectively, for about 30%, 7% and 60% of total AChE activity. Applications of hydrophobic chromatography on phenyl-agarose to three solubilized fractions revealed that hydrophilic forms were almost exclusively located in the LSS fraction ( approximately 27% of total AChE), whereas most amphiphilic forms were present in DS extracts ( approximately 59% of total AChE), the remaining forms being distributed among aqueous soluble fractions. Enzyme molecular forms in the solubilized extracts were identified by centrifugation in 5-20% sucrose gradients containing Triton X-100 or Brij 97 to differentiate between hydrophilic or amphiphilic species. A predominance of hydrophilic dimeric forms ( approximately 22%), with small amounts of hydrophilic monomers (5%) and amphiphilic dimers and monomers (3%), was found in soluble AChE (LSS fraction). Amphiphilic AChE forms extracted in the HSS and DS fractions had a single peak in the sedimentation profiles with sedimentation coefficients of about 6S in gradients with Triton X-100; these were slightly shifted in the presence of Brij 97. After treatment with dithiothreitol, this molecular form solubilized in DS was converted to another molecular form with a lower sedimentation coefficient. Our results show that amphiphilic globular dimers are the dominant molecular form in sheep platelet AChE, suggesting a partial conversion of this membrane-bound form into soluble dimers and monomers, mainly with a hydrophilic character, through the action of either endogenous proteases and phospholipases or residual endogenous reducing agents.


Limitation of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography (FDG-PET) to detect early synchronous primary cancers in patients with untreated head and neck squamous cell cancer.
Patients with head and neck squamous cell carcinoma (HNSCC) often develop synchronous multiple primary cancers. It is important to detect second primary cancer in HNSCC patients, because it influences treatment selection of primary cancer. The aim of this study was to evaluate the utility of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) for detecting synchronous primary cancers at the initial staging of patients with HNSCC. Three hundred and forty-seven patients with untreated HNSCC underwent FDG-PET with or without computed tomography fusion and other routine workups, including upper gastrointestinal Lugol chromoendoscopy, for the initial staging. We examined the prevalence of second primary cancer in these patients and the utility of PET. We identified 57 synchronous primary cancers in 53 patients, of which only 33 % were detected with PET. The most common site for the second primary cancer was the esophagus (49 %), followed by stomach (14 %) and head and neck (11 %). Most early-stage esophageal cancers and stomach cancers were detected using Lugol chromoendoscopy but not PET. Although PET is useful for detecting synchronous primary cancers, it is not a sensitive technique for detecting early esophageal cancers and gastric cancers. Therefore, Lugol chromoendoscopy is indispensable for detecting synchronous upper gastrointestinal cancers in HNSCC patients.


Nucleotide sequence heterogeneity of an RNA phage population.
The nucleotide sequence of 32P-RNA from Q beta phage clones was sampled by two-dimensional polyacrylamide gel electrophoresis of the RNAase T1-resistant oligonucleotides (T1 fingerprinting). About 15% of the clones derived from a multiply passaged Q beta population showed fingerprint patterns which deviated from that of the RNA from the total population. All deviations examined could be attributed to one and, less frequently, to two or more nucleotide transitions. Since the fingerprinting technique allows the analysis of only about 10% of the RNA sequence, we estimate that each viable phage genome in a multiply passaged population differs in one to two positions from the "average" sequence of the parental population. Several deviant clones were tested by growth competition against a "wildtype" population, after 10-20 generations, the resulting phage showed the "wild-type" T1 fingerprint pattern. We propose that a Q beta phage population is in a dynamic equilibrium, with viable mutants arising at a high rate (Batschelet, Domingo and Weissmann, 1976; Domingo, Flavell and Weissmann, 1976) on the one hand, and being strongly selected against on the other. The genome of Q beta phage cannot be described as a defined unique structure, but rather as a weighted average of a large number of different individual sequences.


Enhancement of offset analgesia during sequential testing.
Interruption of a continuous noxious heat by a relatively greater noxious heat evokes reductions in pain experience when the original noxious heat returns. The reduction is greater than that evoked by continuous delivery of noxious heat. This disproportionate reduction in pain experience, known as offset analgesia, is presumably mediated by a mechanism different to adaptation or habituation. Reduction in pain experience to an equivalent noxious stimulus, however, has also been demonstrated when applying the same stimulus over a number of days. This reduction due to repeated days of stimulation is known as attenuation. In order to distinguish further the mechanisms of offset analgesia and attenuation we applied noxious heat resulting in an experience of low, medium or high pain to the volar forearm of 16 subjects comparing pain intensity ratings for increases and decreases in temperature, repeated over 3 days. Offset analgesia was consistently demonstrated but the effects of attenuation were more complex. There was no attenuation effect for the unchanging stimuli delivered across the 3 days of testing but attenuation effects enhanced the offset analgesia resulting in a larger offset analgesia effect on days 2 and 3. It is possible that offset analgesia and attenuation are mediated by inter-related mechanisms. Further studies might investigate whether offset analgesia involves inhibitory structures such as the PAG-RVM.


Agreement in measurements of ultrasonography-derived periodontal diagnostic parameters among multiple raters: A diagnostic accuracy study.
The aim of this study was to investigate the reproducibility of measurements of ultrasound-derived periodontal diagnostic parameters (PDPs) among raters. Periodontists with various degrees of ultrasound experience were invited to measure 3 PDPs: soft tissue height (STH), soft tissue thickness (STT), and crestal bone thickness (CBT) on 37 human periodontal ultrasound scans acquired at the midfacial site of non-molar maxillary teeth. After an online training session and a 2-week calibration exercise, intraclass correlation coefficients (ICCs) were estimated with mixed linear regression models. The interrater mean absolute differences (MADs) were calculated among the raters and between the raters and a reference standard examiner. Thirteen raters participated in the study. MADs among the 13 raters were 0.18 mm (STH), 0.16 mm (STT), and 0.12 mm (CBT). ICC values for STH, STT, and CBT were 0.83, 0.77, and 0.76, respectively. The MADs between the raters and the reference standard were 0.23 mm (STH), 0.19 mm (STT), and 0.14 mm (CBT). Survey results showed that ultrasound has diagnostic value and is generally easy to learn. Within the limitations of this study, good agreement was observed among ultrasound learners with various degrees of experience when measuring ultrasound-derived PDPs.


Persimmon tannin changes the properties and the morphology of wheat gluten by altering the cross-linking, and the secondary structure in a dose-dependent manner.
The effects of persimmon tannin (PT) on the texture, viscoelasticity, thermal stability, and morphology of gluten were studied and the underlying mechanisms were also explored. The results showed that PT increased the hardness and viscoelasticity but lowered the cohesiveness and extensibility of gluten in a dose-dependent manner. Additionally, PT increased the denaturation temperature and enthalpy of gluten, and induced the formation of gluten with compact structure. High concentration of PT (8%) significantly increased the hardness and viscoelasticity of gluten, and induced the formation of compact structure of gluten by disturbing the conformation of gluten, and interfering gluten cross-linking through decreasing disulfide bonds, free sulfydryl groups, and free amino groups. In contrast, low concentration (0.25%) of PT slightly altered the gluten properties and morphology. Our work extended the study on the supplementation of phenolic compounds in wheat flour-based products.


Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.
Recent results suggest that plasma cell longevity is not an intrinsic capacity, but depends on yet unknown factors produced in their environment. In this study, we show that the cytokines IL-5, IL-6, TNF-alpha, and stromal cell-derived factor-1alpha as well as signaling via CD44 support the survival of isolated bone marrow plasma cells. The cytokines IL-7 and stem cell factor, crucially important for early B cell development, do not mediate plasma cell survival, indicating that plasma cells and early B cells have different survival requirements. As shown in IL-6-deficient mice, IL-6 is required for a normal induction, but not for the maintenance of plasma cell responses in vivo, indicating that the effects of individual survival factors are redundant. Optimal survival of isolated plasma cells requires stimulation by a combination of factors acting synergistically. These results strongly support the concept that plasma cell survival depends on niches in which a combination of specific signals, including IL-5, IL-6, stromal cell-derived factor-1alpha, TNF-alpha, and ligands for CD44, provides an environment required to mediate plasma cell longevity.


Rheological behaviors of a novel exopolysaccharide produced by Sphingomonas WG and the potential application in enhanced oil recovery.
A novel exopolysaccharide, named WL gum, was obtained from the fermentation broth of Sphingomonas sp. WG. The effects of temperature and salinity on the rheological properties of WL gum solution and fermentation broth (WL-Fer) were systematically investigated and compared with another exopolysaccharide, welan gum (WG). The results showed that the network structures formed in WL solution were more compact than those of WG. WL solution and WL-Fer were not sensitive to high temperatures (80-120 °C) and only weakly affected by the cations (Na+, K+, and Ca2+). Moreover, Fe2+ and high temperature (100 °C) even enhanced the viscosity of WL-Fer. The results of flooding experiments demonstrated that the enhanced displacement efficiency of WL gum (14.55%) was similar to that of partially hydrolyzed polyacrylamide (HPAM, 13.36%) at 65 °C. And the enhanced displacement efficiency of WL-Fer was as high as 23.31%. It can be concluded that WL gum is a kind of potential and environmentally benign polymer that could be used in EOR, and the fermentation broth could be used directly after dilution.


Recanalization and outcomes after cerebral venous thrombosis: a systematic review and meta-analysis.
Recanalization in cerebral venous thrombosis (CVT) can begin as early as 1 week after initiating therapeutic anticoagulation. The clinical significance of recanalization remains uncertain. We aimed to investigate the association between recanalization and functional outcomes and explored predictors of recanalization. A systematic literature search was conducted (EMBASE, MEDLINE, Cochrane library) to identify: (1) patients with CVT aged ≥18 years treated with anticoagulation only; (2) case series, cohort, or randomized controlled trial studies; and (3) reported recanalization rates and functional outcomes using either a modified Rankin Scale (mRS) or sequelae of CVT at last follow-up. Meta-analysis was performed using pooled odds ratios (ORs) with exploration of sex and age effects using meta-regression. Twenty-three studies were eligible with 1418 individual patients in total. Timing of reimaging and clinical reassessment was variable. Absence of recanalization was associated with increased odds of an unfavorable functional outcome (mRS 2-6 versus 0-1; OR, 3.66; 95% CI, 1.73-7.74; p = 0.001), CVT recurrence (OR, 8.81; 95% CI, 1.63-47.7; p = 0.01), and chronic headache (OR, 2.78; 95% CI, 1.16-6.70; p = 0.02). On meta-regression, the relationship between recanalization and mRS differed by the proportion of female patients, where lower proportions of women were associated with higher likelihood of a worse outcome, but not by mean participant age. There was no incremental benefit of full compared with partial recanalization with respect to favorable mRS or recurrence, but odds of chronic headache were higher with partial versus full recanalization (OR, 3.80; 95% CI, 1.43-10.11; p = 0.008). Epilepsy and visual sequelae were not associated with recanalization. Absence of recanalization was associated with worse functional outcomes, CVT recurrence, and headache, but outcomes were modified by sex. The degree of recanalization was significant in relation to headache outcomes, where partial compared with complete recanalization resulted in a greater likelihood of residual headache. Prospective studies with common timing of repeat clinical-neuroimaging assessments will help to better ascertain the relationship and directionality between the degree of recanalization and outcomes.


Driving Factors of Carbon Emissions in G20 Countries: A Weighted Average Structural Decomposition Approach.
As a major part of global development governance, G20 countries account for 80% of global carbon emissions. In order to achieve the goal of "carbon neutrality" proposed by the United Nations, it is important to compare and analyze the drivers of carbon emissions in G20 countries and provide recommendations for their carbon emission reduction. Based on the data of 17 G20 countries in the EORA database, this paper compares the drivers of carbon emissions of each country from 1990-2021 using weighted average structural decomposition and K-mean model. This paper focuses on four drivers, including carbon emission intensity, final demand structure, export structure, and production structure. Carbon emission intensity and final demand structure are the main factors of carbon emission reduction, and the other two factors have little influence. Among the G20 countries, the UK is in the first category because it does the best job on the four factors of carbon emissions, yet Italy is in the last category because it does not take full advantage of the four factors. Therefore, improving supply energy efficiency and adjusting demand, export, and industrial structure have become important tools for countries to transform and achieve carbon neutrality.


Biosynthesis of gold nanoparticles in the fruiting body of enoki mushrooms (Flammulina velutipes) under Pb2+ induction.
Fungi can produce many compounds, such as proteins, enzymes, amino acids, and polysaccharides, which are internalised and enriched for metals, and are widely used as reducing and stabilising agents for the biosynthesis of gold nanoparticles (Au NPs). Almost all fungal sources used in the synthesis of the Au NPs are in the form of cell filtrates or mycelial suspensions. However, the culture of cell-free fungal filtrate and mycelium is not comparable to the propagation of fungal substrates in input and operation. Here, we evaluated in vivo biosynthesis of Au NPs in enoki mushrooms (Flammulina velutipes). HAuCl4 was reduced in the fruiting body of the enoki mushrooms via induction by Pb2+ , resulting in the generation of Au NPs. We then employed UV-Vis absorption spectroscopy, Transmission Electron Microscope, and Energy Dispersive Spectrometer to characterise various shapes of the Au NPs. The elemental analysis indicated that the Au NPs were mainly concentrated in organelles of the stalk and cap cells. We also demonstrated that 0.3-0.5 mM HAuCl4 was the optimal stress treatment concentration based on the changes in physiological indicators of the enoki mushrooms. This work reveals that fungi can be utilised well as nanomaterial bioreactors.


Reproductive Outcomes After Breast Cancer in Women With vs Without Fertility Preservation.
The practice of fertility preservation (FP) in women with breast cancer (BC) is spreading, but long-term reproductive outcomes after FP are largely unknown. To investigate the long-term reproductive outcomes in women who did or did not undergo FP at the time of BC diagnosis. A Swedish nationwide cohort study was conducted to investigate the long-term reproductive outcomes of women with BC receiving FP at 1 of the regional FP programs from 1994 to 2017 (n = 425). Population comparators with BC but without history of FP (n = 850) were sampled from regional BC registers, matched on age, calendar period of diagnosis, and county. Data on live births, assisted reproductive technology (ART) use, and mortality were retrieved from population-based registers. Data analysis was performed from January to September 2020. History of having received FP compared with no history of FP (unexposed). The primary outcome was hazard ratios (HRs) of live births and ART treatments following BC in women with vs without FP and the cumulative incidence of these events in the presence of the competing risk of death. Women who had undergone FP (n = 425) had lower parity (302 [71.1%] were nulliparous compared with 171 [20.1%] in the unexposed group), were younger (mean [SD] age, 32.1 [4.0] vs 33.3 [3.6] years), more often had estrogen receptor-positive tumors (289 [68.0%] vs 515 [60.6%]), and were more often scheduled for chemotherapy (399 [93.9%] vs 745 [87.7%]). Of 425 women exposed to FP, 97 (22.8%) had at least 1 post-BC live birth (mean follow-up, 4.6 years), compared with 74 of 850 women (8.7%) unexposed to FP (mean follow-up, 4.8 years). Overall, live birth rates after BC were significantly higher among women with FP (adjusted hazard ratio [aHR], 2.3; 95% CI, 1.6-3.3). The 5-year and 10-year cumulative incidence of post-BC live births was 19.4% and 40.7% among FP-exposed women vs 8.6% and 15.8% among comparators, respectively. Rates of ART use were also higher in the FP group (aHR, 4.8; 95% CI, 2.2-10.7). The all-cause mortality rate was lower in women exposed to FP (aHR, 0.4; 95% CI, 0.3-0.7), with 5-year cumulative incidence of death of 5.3% (95% CI, 3.1%-9.0%) vs 11.1% (95% CI, 8.7%-14.1%) for women with vs without FP. In this cohort study of Swedish women after a BC diagnosis, successful pregnancy after BC was possible both in women with and without FP at the time of diagnosis, but a significantly higher likelihood of post-BC live births and ART treatments was observed in women who underwent FP, without any negative association with all-cause survival. This information is valuable for health care clinicians responsible for oncologic treatment and reproductive counseling of women diagnosed with breast cancer at reproductive age.


New species of Oideterus Thomson (Coleoptera, Cerambycidae, Prioninae, Anacolini) and notes on O. lobicollis.
Oideterus inaequalis sp. nov. is described from Ecuador and compared with the holotype of O. lobicollis. The latter is excluded from the fauna of Ecuador. A key to known females of Oideterus is provided.


Attitudes towards the sharing of genetic information with at-risk relatives: results of a quantitative survey.
To investigate public attitudes towards receiving genetic information arising from a test on a relative, 955 University of Sheffield students and staff were surveyed using disease vignettes. Strength of attitude was measured on whether, in the event of relevant information being discovered, they, as an at-risk relative, would want to be informed, whether the at-risk relative's interest should override proband confidentiality, and, if they had been the proband, willingness to give up confidentiality to inform such relatives. Results indicated considerably more complexity to the decision-making than simple statistical risk. Desire for information only slightly increased with risk of disease manifestation [log odds 0.05 (0.04, 0.06) per percentage point increase in manifestation risk]. Condition preventability was the primary factor increasing desire [modifiable baseline, non-preventable log odds -1.74 (-2.04, -1.44); preventable 0.64 (0.34, 0.95)]. Disease seriousness also increased desire [serious baseline, non-serious log odds -0.89 (-1.19, -0.59); fatal 0.55 (0.25, 0.86)]. Individuals with lower education levels exhibited much greater desire to be informed [GCSE log odds 1.67 (0.64, 2.66)]. Age did not affect desire. Our findings suggest that attitudes were influenced more by disease characteristics than statistical risk. Respondents generally expressed strong attitudes demonstrating that this was not an issue which people felt ambivalent about. We provide estimates of the British population in favour/against disclosure for various disease scenarios.


Evaluation of the anticholinesterase activity of metronidazole and misonidazole.
Contrary to an earlier report that metronidazole exhibited anticholinesterase activity on isolated organ preparations, a direct spectrophotometric assay was unable to demonstrate any significant inhibition of either true or pseudocholinesterase activity in the presence of this drug. The related nitroimidazole, misonidazole, was also found to be inactive when tested in this system. This report demonstrates that the clinical neurotoxicity of these two compounds cannot be attributed to any direct effect on the cholinesterase enzymes.


Tunneling technique for anatomical positioning of aortoaxillary bypass graft.
A technique for anatomical positioning of a synthetic aortoaxillary bypass tube graft is described. A tunnel is created with the help of a Roberts clamp and intercostal tube drain. There is no need to open the pleura because the graft is tunneled parallel to the subclavian vessels outside the chest cavity.


Diagnostic Accuracy of the Defining Characteristics of Impaired Swallowing in Children with Encephalopathy.
The purpose of this study was to analyze the accuracy of the defining characteristics of the nursing diagnosis of impaired swallowing in children with encephalopathy. The measures of diagnostic accuracy for each indicator were verified through latent class analysis. The prevalence of swallowing impairment was 59.76% for a total of 82 children evaluated. The defining characteristics that had good measures of sensitivity (range: 79.59-99.99) and specificity (range: 72.72-99.99) were as follows: food falls from the mouth, tongue action ineffective in forming bolus, prolonged bolus formation, inability to clear the oral cavity, and food refusal. Eight characteristics can be used as warning signs for impaired swallowing because they have high sensitivity values. In addition, ten characteristics presented high specificity and can be used to confirm this diagnosis in children with encephalopathy. Considering the findings of the swallowing pattern assessments through the analysis of the accuracy measures, it is verified that the evidence presented here should guide the pediatrics nurses in the diagnosis decision making. Indicators of high sensitivity should be used as warning signs for swallowing impairment, and the high specificity indicators should be used as a confirmatory sign of this condition and requires immediate intervention.


First-contact incidence of psychosis in north-eastern Italy: influence of age, gender, immigration and socioeconomic deprivation.
Considerable variations in the incidence of psychosis have been observed across countries, in terms of age, gender, immigration status, urbanicity and socioeconomic deprivation. To evaluate the incidence rate of first-episode psychosis in a large area of north-eastern Italy and the distribution of the above-mentioned risk factors in individuals with psychoses. Epidemiologically based survey. Over a 3-year period individuals with psychosis on first contact with services were identified and diagnosed according to ICD-10 criteria. In total, 558 individuals with first-episode psychosis were identified during 3,077,555 person-years at risk. The annual incidence rate per 100,000 was 18.1 for all psychoses, 14.3 for non-affective psychoses and 3.8 for affective psychoses. The rate for all psychoses was higher in young people aged 20-29 (incidence rate ratio (IRR) = 4.18, 95% CI 2.77-6.30), immigrants (IRR = 2.26, 95% CI 1.85-2.75) and those living in the most deprived areas (IRR = 2.09, 95% CI 1.54-2.85). The incidence rate in our study area was lower than that found in other European and North American studies and provides new insights into the factors that may increase and/or decrease risk for developing psychosis.


The family environment of sexual abuse: a comparison of natal and stepfather abuse.
Data from 17 states, drawn from the 1983 National Study on Child Neglect and Reporting, were used to compare families in which a daughter had been sexually abused by a natal father or stepfather. While broad comparisons are made in terms of age and race of victims, as well as household composition, the primary focus is on familial stress factors. Given the lower incidence of natal father abuse and the assumption that natal fathers have stronger emotional links to their children and greater commitment to the father role, we predicted that when they did engage in sexual abuse, it would be in a family environment characterized by relatively high levels of personal, social, and economic stress. This was confirmed to the extent that natal father abuser families showed significantly higher levels of drug and/or alcohol abuse, marital problems, and insufficient income than did stepfather abuser families.


Science, Technology, and Human Health: The Value of STS in Medical and Health Humanities Pedagogy.
As the number of medical and health humanities degree programs in the United States rapidly increases (Berry, Lamb and Jones 2016, 2017), it is especially timely to consider the range of specific disciplinary (and multidisciplinary) perspectives that might benefit students enrolled in these programs. This paper discusses the inclusion of one such perspective from the field of Science and Technology Studies (STS.) The author asserts that STS benefits students in the medical and health humanities in four particular ways, by: (1) challenging the "progress narrative" around the advancement of biomedicine as scientific practice, (2) evaluating the meaning of technology, especially in how technology orients us towards sickness and how health technology is in turn shaped by social and cultural values, (3) assessing the plurality of biomedical epistemologies, rather than assuming biomedicine is one, cohesive body of knowledge that does not differ across contexts, and (4) critiquing bias in biomedical practice and science, especially in the marginalization of women's voices and in the racial and postcolonial trajectories of contemporary biomedicine. The paper discusses the theoretical importance of these four trajectories to the medical and health humanities, as well as the venues for inclusion of STS within coursework and programming at Case Western Reserve University. The paper also comments on how programming at other institutions might be adapted to incorporate STS scholarship. By drawing on numerous examples of research in the anthropology, sociology, history, and the philosophy of science, this article seeks to open a conversation about the value of science and technology studies to health humanities pedagogy.


[The comparative analysis of the complications of extracapsular cataract extraction with and without posterior chamber intraocular lens implantation].
Three-hundred and fourteen eyes that underwent extracapsular cataract extraction (ECCE) were analyzed. ECCE with posterior chamber intraocular lens implantation (PC IOL) was performed in 168 eyes and ECCE alone was performed in 146 eyes. The complications and visual acuity were compared in the two groups. The PC IOL group showed a low incidence of complications. In addition, vitreous loss occurred in 2.38%, cystoid macular edema occurred in 0.6%, and visual acuity recovered to 0.5 or better in 97.62% of the eyes. The incidence of complications in the ECCE group was slightly higher. The postoperative visual acuity in the ECCE group was lower than that in PC IOL group.


[Carcinoma in situ detected by contralateral testicular biopsy of 55 germ cell tumor patients].
We performed contra-lateral testicular biopsies in 55 testicular tumor patients when high orchiectomy was performed. In these cases, two cases developed invasive testicular tumor later although the biopsies had not revealed testicular CIS. Then we re-examined the sensitivity of biopsies and judged if our results are contradictory against Skakkebaek's theory. The paraffin blocks of two cases who later developed testicular tumor were sliced again and re-examined by H/E staining and immunostaining with PLAP antibody (clone No. 8A9). The other 53 H/E samples were re-examined and the result of the contra-lateral testis was re-searched in the case that CIS was detected in the specimen. CIS was detected in one of the two cases who later developed contra-lateral testicular tumor and another case among the other 53 cases. We could not reveal the result of the testis of case No. 3 because of the patient's disappearance. CIS existed 3.6% (2/55) and two cases were found to have been false negative. It is important for both urologists and pathologists to know well about testicular CIS and to perform biopsy according to Skakkebaek's guidance for raising the sensitivity to detect testicular CIS.


Prognosis prediction of icotinib as targeted therapy for advanced EGFR-positive non-small cell lung cancer patients.
Clinical trials on icotinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), have shown promising results as targeted therapy for non-small cell lung cancer (NSCLC). This study aimed to establish an effective scoring system to predict the one-year progression-free survival (PFS) of advanced NSCLC patients with EGFR mutations treated with icotinib as targeted therapy. A total of 208 consecutive patients with advanced EGFR-positive NSCLC treated with icotinib were enrolled in this study. Baseline characteristics were collected within 30 days before icotinib treatment. PFS was taken as the primary endpoint and the response rate as the secondary endpoint. Least absolute shrinkage and selection operator (LASSO) regression analysis and Cox proportional hazards regression analysis were used to select the optimal predictors. We evaluated the scoring system using a five-fold cross-validation. PFS events occurred in 175 patients, with a median PFS of 9.9 months (interquartile range, 6.8-14.5). The objective response rate (ORR) was 36.1%, and the disease control rate (DCR) was 67.3%. The final ABC-Score consisted of three predictors: age, bone metastases and carbohydrate antigen 19-9 (CA19-9). Upon comparison of all three factors, the combined ABC-score (area under the curve (AUC)= 0.660) showed a better predictive accuracy than age (AUC = 0.573), bone metastases (AUC = 0.615), and CA19-9 (AUC = 0.608) individually. A five-fold cross-validation showed good discrimination with AUC = 0.623. The ABC-score developed in this study was significantly effective as a prognostic tool for icotinib in advanced NSCLC patients with EGFR mutations.


Dosimetric comparison between three-dimensional conformal radiotherapy followed by electron beam boost and volumetric modulated arc therapy using concomitant boost for the heart and cardiac segments in patients with left-sided breast cancer at risk for radiation-induced cardiac toxicity.
We aimed to compare dosimetric parameters between three-dimensional conformal radiation therapy followed by electron beam boost (3D-CRT + EB) and volumetric modulated arc therapy using simultaneous integrated boost (SIB-VMAT) in left-sided breast cancer patients. This study included 57 patients with left-sided breast cancer who underwent SIB-VMAT. All patients had a computed tomography-based maximum heart distance of ≥ 1 cm and were prescribed a dose of 42.56 Gy/16 fractions to the planning target volume and a concomitant-boosted target dose of 53.2 Gy or 51.2 Gy. The 3D-CRT + EB plan was retrospectively created for the purpose of comparison using tangential fields with field-in-field technique followed by electron beam irradiation. The doses to the clinical target volume significantly improved in the SIB-VMAT plans. All dosimetric parameters for the left anterior descending coronary artery (LAD) and LAD middle position (LAD mid) in the SIB-VMAT plans were significantly lower than those for 3D-CRT + EB plans (P < 0.01), while the doses to the heart, lung, contralateral breast and non-target tissue were decreased in the 3D-CRT + EB plans compared with those in the SIB-VMAT plans (e.g., 1.9 Gy vs. 2.9 Gy; P < 0.001 for the mean dose of heart). SIB-VMAT significantly improved the dose to the target while reducing the doses to the LAD and LAD mid, whereas 3D-CRT + EB significantly decreased the doses to the heart and other organs at risk in patients with left-sided breast cancer at risk for radiation-induced coronary artery disease.


[Clinical observation on effect of total glucosides of paeony combined with methotrexate on rheumatoid arthritis].
To observe the effect of total glucosides of paeony (TGP) combined with methotrex-ate (MTX) on rheumatoid arthritis (RA). Two hundred and sixty patients were assigned to two groups, the treated group (180 cases) was orally administered with MTX plus TGP, and the control group (80 cases) with MTX plus sulfasalazine (SSZ). The therapeutic course for both groups was 24 weeks. The clinical effect and the indexes for RA were observed after treatment. The total effective rate at the 4th, 8th, 12th, 24th week of the treatment was 70%, 81%, 94%, 98% in the treated group, and 60%, 85%, 93%, 94% in the control, respectively, with insignificant difference found between the two groups (P > 0.05). Various indexes of RA were markedly improved in both two groups after treatment but the improvement in the treated group was better than that in the control group (P < 0.05). TGP combined MTX treatment shows favorable effect on RA, showing a quicker initiation with less side-effect and higher compliance.


Differences in the association between type 2 diabetes and impaired microvascular function among Europeans and African Caribbeans.
Diabetes is associated with microvascular damage in all populations, but diabetic patients of Black African descent (African Caribbeans) have a greater risk of vascular target organ damage than would be anticipated for any given blood pressure level. We investigated whether this may be due to differences in the microvasculature. To assess the maximum hyperaemic response to heating and the post-ischaemic response, Laser Doppler fluximetry was performed on 51 and 100 Europeans, and on 66 and 88 African Caribbeans with and without diabetes, respectively. Subjects were aged between 40 and 65 years and recruited from the general population. Echocardiographic interventricular septal thickness (IVST) was measured as a proxy for vascular target organ damage. In diabetic subjects of both ethnic groups, the maximum hyperaemic response and peak response to ischaemia were attenuated as compared to the corresponding non-diabetic subjects (p=0.08 for diabetic and 0.03 for non-diabetic Europeans; p=0.03 and 0.1 for African Caribbeans). Adjustment for cardiovascular risk factors, in particular insulin and blood pressure, abolished these differences in Europeans (p=0.8 for diabetic and 0.2 for non-diabetic Europeans), but not in African Caribbeans (p=0.03 and 0.05). Persisting microvascular dysfunction in African Caribbeans may contribute to the increased risk of target organ damage observed in diabetes in this population. The weak contribution of conventional cardiovascular risk factors to these disturbances indicates that conventional therapeutic interventions may be less beneficial in these patients. There was a risk-factor-independent, inverse association between IVST and maximal hyperaemia. These ethnic differences in microvascular responses to temperature and arterial occlusion could account for increased target organ damage in African Caribbeans.


Oral administration of a Bacillus subtilis spore-based vaccine expressing Clonorchis sinensis tegumental protein 22.3 kDa confers protection against Clonorchis sinensis.
Human clonorchiasis, caused by the infection of Clonorchis sinensis, is endemic in China. In this study, a full-length cDNA sequence encoding C. sinensis tegumental protein 22.3 kDa (CsTP22.3) was identified from adult cDNA library. Recombinant CsTP22.3 was expressed and purified from Escherichia coli BL21. CsTP22.3 was immunolocalized at the tegument of adult C. sinensis by using anti-recombinant CsTP22.3 sera. ELISA was performed using rCsTP22.3 protein to investigate the IgG response to CsTP22.3. Sera from clonorchiasis patients had clear IgG response to CsTP22.3. We used the CotC, a major component of the Bacillus subtilis spore coat, as a fusion partner for the expression of C. sinensis TP22.3 on the spore coat. Western blotting and immunofluorescence analyses were used to identify TP22.3 surface expression on spores. Recombinant spores displaying the TP22.3 antigen were used for oral immunization and were shown to generate mucosal response in rats. TP22.3-specific secretory IgA in faeces reached significant levels 2 weeks after oral dosing. In addition, the recombinant spores induced a significant level of protection (44.7%, p<0.05) in rats challenged with C. sinensis metacercariae. This report shows that C. sinensis TP22.3 expressed on B. subtilis spores was immunogenic and oral administration of TP22.3 spore can provide protection against C. sinensis.


Robust contrast-transfer-function phase retrieval via flexible deep learning networks: publisher's note.
This publisher's note contains corrections to Opt. Lett.44, 5141 (2019)OPLEDP0146-959210.1364/OL.44.005141.


Activation of cytomegalovirus-specific CD8+ T-cell response by antibody-mediated peptide-major histocompatibility class I complexes.
Imposing antigenicity on tumor cells is a key step toward successful cancer-immunotherapy. A cytomegalovirus-derived peptide recombinantly fused to a major histocompatibility class I complex and a monoclonal antibody can be targeted to tumor cells by antibody-mediated delivery and activate a strong and specific CD8+ T cell response.


Radioactive and nonradioactive methods for the in vivo determination of disulfiram, diethyldithiocarbamate, and diethyldithiocarbamate-methyl ester.
Although disulfiram (tetraethylthiuram disulfide; DSF) has been used in the treatment of alcoholism for almost a quarter of a century, little is known about its in vivo metabolism. One reason for this is that few analytical methods are available that can determine DSF and its various metabolites in biologic fluids and tissues. This article describes two simple procedures for the determination of these substances.


[Quchiling water extract inhibits secretion of beta-amyloid protein by M146L cell].
To approach the possibility and mechanism that Quchiling treats Alzheimer' s disease (AD), we studied the effect of Quchiling water extract-contained serum (QCS) on the secretion of beta-amyloid protein 42 (Abeta42) by Chinese hamster ovary cells which stably express beta-amyloid protein precursor (APP) and mutant preseinlin 1 (M146L). The QCS was prepared using rats. The cell model, M146L, producing beta-amyloid protein in vitro was established by transfecting APP and mutant presenilin-1 genes. The mononuclear cell directed cytotoxicity assay (MTF) test and enzyme linked immunosorbent assay (ELISA) were performed to evaluate the effect of the QCS on the cell model and to analyse Abeta42 secretion. The MTT test indicated that different concentrations of the QCS had no effect on the cultured M146L cell survival. And the ELISA test showed that the secretion of Abeta42 by the M146L cell decreased obviously. The suitable dose of the QCS can inhibit the secretion of Abeta42 by M146L cell, and its mechanism will be further studied.


Differences in therapy and survival between lung cancer patients treated in hospitals with high and low patient case volume.
In light of political discussions about minimum case volumes and certified lung cancer centers, this observational study investigates differences in therapy and survival between high vs. low patient volume hospitals (HPVH vs. LPVH). We identified 12,374 lung cancer patients treated in HPVH (>67 patients) and LPVH in 2013 from German health insurance claims. Stratified by metastasis status (no metastases, nodal metastases, systemic metastases), we compared HPVHs and LPVHs regarding likelihood of resection and systemic therapy, type of systemic therapy, and surgical outcomes, using multivariate logistic models. Three-year survival was modeled using Cox regression. We adjusted all regression models for age, gender, comorbidity, and residence area, and included a cluster variable for the hospital. Around 24 % of patients were treated in HPVHs. Irrespective of stratum and subgroup, three-year survival was significantly better in HPVHs. In patients with systemic metastases (OR = 1.84, CI=[1.22,2.76]) and without metastases (OR = 3.28, CI=[2.13, 5.04]), resection was more likely in HPVHs. Among patients with systemic therapy, the odds of receiving pemetrexed was higher in HPVHs, in patients with nodal metastases (OR = 1.57, CI=[1.01,2.45]). In resected patients without metastases the odds ratio of receiving a thoracoscopic lobectomy was 2.28 (CI=[1.04,4.99]) in HPVHs. Our data suggests that case volume is clinically relevant in resected and non-resected lung cancer patients, but optimal minimum case volumes may differ for subgroups.


Prediction of Axillary Lymph Node Metastasis in Early-stage Triple-Negative Breast Cancer Using Multiparametric and Radiomic Features of Breast MRI.
To investigate whether machine learning (ML) approaches using breast magnetic resonance imaging (MRI)-derived multiparametric and radiomic features could predict axillary lymph node metastasis (ALNM) in stage I-II triple-negative breast cancer (TNBC). Between 2013 and 2019, 86 consecutive patients with TNBC who underwent preoperative MRI and surgery were enrolled and divided into ALNM (N = 27) and non-ALNM (n = 59) groups according to histopathologic results. For multiparametric features, kinetic features using computer-aided diagnosis (CAD), morphologic features, and apparent diffusion coefficient (ADC) values at diffusion-weighted images were evaluated. For extracting radiomic features, three-dimensional segmentation of tumors using T2-weighted images (T2WI) and T1-weighted subtraction images were respectively performed by two radiologists. Each predictive model using three ML algorithms was built using multiparametric features or radiomic features, or both. The diagnostic performances of models were compared using the DeLong method. Among multiparametric features, non-circumscribed margin, peritumoral edema, larger tumor size, and larger angio-volume at CAD were associated with ALNM in univariate analysis. In multivariate analysis, larger angio-volume was the sole statistically significant predictor for ALNM (odds ratio = 1.33, P = 0.008). Regarding ADC values, there were no significant differences according to ALNM status. The area under the receiver operating characteristic curve for predicting ALNM was 0.74 using multiparametric features, 0.77 using radiomic features from T1-weighted subtraction images, 0.80 using radiomic features from T2WI, and 0.82 using all features. A predictive model incorporating breast MRI-derived multiparametric and radiomic features may be valuable in predicting ALNM preoperatively in patients with TNBC.


Optimal insulin infusion resulting from a mathematical model of blood glucose dynamics.
Mathematical optimization techniques are applied to a simplified mathematical model of blood glucose dynamics to derive insulin infusion programs for the control of blood glucose levels in diabetic individuals. Two particular cases are discussed. First, the insulin infusion program which results in an initially high blood glucose level being reduced to acceptable levels. Second, the control of blood glucose levels following a meal, prior to which blood glucose and net blood-glycemic hormone were at their fasting levels.


Survivin-mediated therapeutic efficacy of gemcitabine through glucose-regulated protein 78 in hepatocellular carcinoma.
Survivin is an antiapoptotic molecule that is widely expressed in cancers, including hepatocellular carcinoma (HCC). Survivin has become a general therapeutic target for cancers because of its selective overexpression in a majority of tumors. However, little is known regarding the effect of survivin expression in combination with gemcitabine on HCC. We generated survivin knockdown cells (survivin-KD) via a short interfering RNA (siRNA) technique. The antiproliferation effects of gemcitabine were determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assay, and cell cycle evaluation. According to the MTT assay, we found that survivin-KD cells were more sensitive than parental cells and scrambled control cells to gemcitabine treatment. The apoptotic cell population increased in survivin-KD cells that were treated with gemcitabine in comparison to scrambled control cells, as observed by the cell cycle distribution and TUNEL assays. We found that survivin knockdown resulted in a reduction of glucose-regulated protein 78 (GRP78), which may be responsible for the observed increased survivin-KD cell sensitivity to gemcitabine. We conclude that survivin knockdown may contribute to a therapeutic effect of gemcitabine through GRP78 on HCC cells.


Activation of the PERK branch of the unfolded protein response during production reduces specific productivity in CHO cells via downregulation of PDGFRa and IRE1a signaling.
During the course of biopharmaceutical production, heterologous protein expression in Chinese hamster ovary (CHO) cells imposes a high proteostatic burden that requires cellular adaptation. To mitigate such burden, cells utilize the unfolded protein response (UPR), which increases endoplasmic reticulum (ER) capacity to accommodate elevated rates of protein synthesis and folding. In this study, we show that during production the UPR regulates growth factor signaling to modulate growth and protein synthesis. Specifically, the protein kinase R-like ER kinase (PERK) branch of the UPR is responsible for transcriptional down-regulation of platelet-derived growth factor receptor alpha (PDGFRa) and attenuation of the IRE1-alpha (IRE1a) branch of the UPR. PERK knockout (KO) cell lines displayed reduced growth and viability due to higher rates of apoptosis despite having stabilized PDGFRa levels. Knocking out PERK in an apoptosis impaired (Bax/Bak double KO) antibody-expressing cell line prevented apoptotic cell death and revealed that apoptosis was likely triggered by increased ER stress and reactive oxygen species levels in the PERK KO hosts. Our findings suggest that attenuation of IRE1a and PDGFRa signaling by the PERK branch of the UPR reduces ER protein folding capacity and hence specific productivity of CHO cells in order to mitigate UPR and prevent apoptotic cell death. Last, Bax/Bak/PERK triple KO CHO cell lines displayed 2-3 folds higher specific productivity and titer (up to 8 g/L), suggesting that modulation of PERK signaling during production processes can greatly improve specific productivity in CHO cells.


Existence of infective juveniles in the offspring of first- and second-generation adults of Steinernema rarum (OLI strain): evaluation of their virulence.
Descriptions of the life cycle of the genus Steinernema do not consider the production of infective juveniles (IJs) by the first-generation developed within the insect host when more than one generation develops. We demonstrated IJ production by first- and second-generation adults of Steinernema rarum (OLI strain), evaluated their virulence and compared virulence and morphometric characters between the two IJ forms. Our results demonstrated not only the presence of IJs in the offspring of first- and second-generation adults but also a greater virulence of first-generation IJs. Both types of IJs also differed in five morphometric characters. According to our results, a population of IJs emerging from a host cadaver has individuals of two generations with different characteristics; hence, they should not be considered the same. These generational differences may be exploited, for example, for biocontrol purposes, by using a specific generation of IJs for inoculative release.


Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway.
Application of silica nanoparticles (SiO2-NPs) may result in human exposure. Here we investigate unexplored modes of action by which SiO2-NPs with average size of 225 nm act on human hepatoma cells (Huh7). We focused on the endoplasmic (ER) stress response and on mitogen-activated protein kinase (MAPK) signaling pathways. Both pathways were induced. ER stress and the associated three unfolded protein response (UPR) pathways were activated as demonstrated by significant inductions of BiP and XBP-1s and a moderate but significant induction of ATF-4 at 0.05 and 0.5 mg/ml. In addition to activation of NFкB interferon stimulated genes IP-10, IRF-9, and ISG-15 were up-regulated. As a consequence of ER stress, the pro-inflammatory cytokine TNFα and PP2Ac were induced following exposure to 0.05 mg/ml SiO2-NPs. Additionally, this occurred at 0.005 mg/ml SiO2-NPs for TNFα at 24 h. This in turn led to a strong transcriptional induction of MAP-kinases and its target genes cJun, cMyc and CREB. A strong transcriptional down-regulation of the proapoptotic gene p53 occurred at 0.05 and 0.5 mg/ml SiO2-NP. Exposure of Huh7 cells to the anti-oxidant N-acetyl cysteine reduced transcriptional induction of ER stress markers demonstrating a link between the induction of oxidative stress and ER stress. Our study demonstrates that SiO2-NPs lead to strong ER stress and UPR induction, oxidative stress, activation of MAPK signaling and down-regulation of p53. All of these activated pathways, which are analyzed here for the first time in detail, inhibit apoptosis and induce cell proliferation, which may contribute to a hepatotoxic, inflammatory and tumorigenic action of SiO2-NPs.


White-matter microstructural properties of the corpus callosum: test-retest and repositioning effects in two parcellation schemes.
We investigated test-retest reliability of two MRI-derived indices of white-matter microstructural properties in the human corpus callosum (CC): myelin water fraction (MWF) and geometric mean T2 relaxation time of intra/extracellular water (geomT2IEW), using a 3D gradient and multi spin-echo sequence in 20 healthy adults (aged 24-69 years, 10 men). For each person, we acquired two back-to-back acquisitions in a single session, and the third after a break and repositioning the participant in the scanner. We assessed the contribution of session-related variance to reliability, using intra-class effect decomposition (ICED) while comparing two CC parcellation schemes that divided the CC into five and ten regions. We found high construct-level reliability of MWF and geomT2IEW in all regions of both schemes, except the posterior body-a slender region with a smaller number of large myelinated fibers. Only in that region, we observed significant session-specific variance in the MWF, interpreted as an effect of repositioning in the scanner. The geomT2IEW demonstrated higher reliability than MWF across both parcellation schemes and all CC regions. Thus, in both CC parcellation approaches, MWF and geomT2IEW have good test-retest reliability and are, therefore, suitable for longitudinal investigations in healthy adults. However, the five-region scheme appears more appropriate for MWF, whereas both schemes are suitable for geomT2IEW studies. Given the lower reliability in the posterior body, which may reflect sensitivity to the repositioning of the participant in the scanner, caution should be exercised in interpreting differential findings in that region.


Pegloticase efficacy and safety in kidney transplant recipients; results of the phase IV, open-label PROTECT clinical trial.
Kidney transplant (KT) recipients have a high prevalence and severity of gout. Pegloticase (pegylated recombinant uricase) rapidly metabolizes serum uric acid (sUA), and its efficacy is not impacted by kidney function. This open-label, Phase 4 trial (PROTECT NCT04087720) examined safety and efficacy of pegloticase in 20 participants with KT > 1 year prior to enrollment and with uncontrolled gout (sUA ≥7 mg/dL, intolerance/inefficacy to urate lowering therapy, and ≥1 of the following: tophi, chronic gouty arthritis, ≥2 flares in past year) and functioning KT (estimated glomerular filtration rate [eGFR] ≥15 mL/min/1.73 m2 ) on stable immunosuppression therapy. The primary endpoint was sUA response during month 6 (sUA < 6 mg/dL for ≥80% of time). The study enrolled 20 participants (mean ± SD); age: 53.9 ± 10.9 years, time since KT: 14.7 ± 6.9 years, sUA: 9.4 ± 1.5 mg/dL, gout duration: 8.4 ± 11.6 years; all on ≥2 stable doses of immunosuppression agents. Pegloticase (8 mg intravenous every 2 weeks) in KT recipients with uncontrolled gout showed a high response rate of 89% (16/18 responders). Two participants discontinued treatment solely due to COVID-19 concerns prior to month 6 were not included in the primary analysis. Pegloticase exposures were higher than those historically observed with pegloticase monotherapy, and no anaphylaxis or infusion reaction events occurred during the study. This improved response rate to pegloticase in the KT population reflects observations from other trials and reports on immunomodulation with pegloticase. As the KT population has a high prevalence of gout and limitations with oral urate lowering medication options, these findings suggest a potential option for uncontrolled gout therapy in KT participants.


Effect of diabetes mellitus on amniotic fluid lecithin/sphingomyelin ratio and respiratory distress syndrome.
Ninety-eight insulin-dependent diabetic patients were cared for during 108 pregnancies following an ambulatory program aimed at close control of blood sugar levels. The incidence of respiratory distress syndrome (RDS) in these patients was not different from that in nondiabetic patients. Fetal pulmonary maturity seemed to progress at a normal rate as evidenced by an equal incidence of mature lecithin/sphingomyelin (L/S) ratios at various stages of gestation in diabetic and nondiabetic patients. There was no evidence that Class B and C diabetic patients have delayed fetal lung maturation or that Class E, F, and R patients have accelerated maturation. It is concluded that careful metabolic control of the pregnant diabetic patient results in a normal process of fetal pulmonary maturation without increased risk of RDS.


The dual role of ferroptosis in anthracycline-based chemotherapy includes reducing resistance and increasing toxicity.
In conjunction with previous studies, we have noted that ferroptosis, as an emerging mode of regulated cell death (RCD), is intimately related to anthracycline pharmacotherapy. Not only does ferroptosis significantly modulate tumour resistance and drug toxicity, which are core links of the relevant chemotherapeutic process, but it also appears to play a conflicting role that has yet to be appreciated. By targeting the dual role of ferroptosis in anthracycline-based chemotherapy, this review aims to focus on the latest findings at this stage, identify the potential associations and provide novel perspectives for subsequent research directions and therapeutic strategies.


Data trimming procedure can eliminate bilingual cognitive advantage.
Bilingualism and its cognitive impacts have drawn increasing interest. Recently, inconsistencies in the findings have raised discussions on what might have caused such discrepancies and how evidence should be evaluated. This review tries to shed new light onto the reasons for the inconsistencies by taking a novel perspective. Motivated by the finding that bilingualism affects response time distribution profiles, particularly findings that suggest bilinguals have fewer long responses, we investigated the relation between maximum response times allowed/included in the analysis of an experiment and the finding of a bilingual advantage. We reviewed 68 experiments from 33 articles that compared monolingual and bilingual speakers' performance in three commonly used non-verbal interference tasks (Simon, Spatial Stroop and Flanker). We found that studies that included longer responses in their analysis were more likely to report a bilingualism effect. We conclude that seemingly insignificant details such as the data trimming procedure can have a potential impact on whether an effect is observed. We also discuss the implication of our findings and suggest the usefulness of more fine-grid analytical procedures.


Changes in prevalence of influenza vaccination and strength of association of factors predicting influenza vaccination over time--results of two population-based surveys.
Two cross-sectional population-based telephone surveys interviewed 877 and 1,103 respondents aged >or=65. When compared to the first survey, respondents of the second survey were more likely to have heard of influenza vaccination (IV) (adjusted OR=4.09), to have received IV (adjusted OR=2.04) or to have done so in the last 6 months (adjusted OR=1.53), and to perceive IV as efficacious (adjusted OR=1.63). The strength of associations between predictors and IV outcomes differed in the two surveys; e.g., OR between perceived health impact and ever having received IV were, respectively, 1.11 (p>0.05) versus 1.91 (p<0.05). IV-related behaviors and perceptions therefore changed over time.


[Synthesis of tyrosin O-sulfate-containing peptides (author's transl)].
A new synthetic route to tyrosine-O-sulfate-containing peptides based on the direct use of N alpha-acyltyrosine-O-sulfate is described and exemplified by the synthesis of the [Thr28,Leu31]cholecystokinin-pankreozymin-(25-33)-nonapeptide.


Genera of the Scirtothrips genus-group (Thysanoptera, Thripidae) with a new species of Siamothrips from Malaysia.
The Scirtothrips genus-group is here considered to comprise 11 genera, and an identification key to these is presented. These genera are Ajothrips Bhatti, Anascirtothrips Bhatti, Biltothrips Bhatti, Cercyothrips Morgan, Drepanothrips Uzel, Ephedrothrips zur Strassen, Kenyattathrips Mound, Parascirtothrips Masumoto & Okajima, Scirtidothrips Hood, Scirtothrips Shull and Siamothrips Okajima. One genus, Sericopsothrips Hood, is considered a new synonym of Scirtothrips, with the only species now referred to as Scirtothrips palloris (Hood) comb.n. A second species in the genus Siamothrips is described from Malaysia as Siamothrips initium sp.n.


miR-218-5p and miR-320a-5p as Biomarkers for Brain Disorders: Focus on the Major Depressive Disorder and Parkinson's Disease.
Depression is one of the early and most persistent non-motor symptoms of Parkinson's disease (PD), which remains ignored, resulting in the underdiagnosis of PD. Unfortunately, scarce studies and the non-availability of diagnostic strategies cause countless complications, highlighting the need for appropriate diagnostic biomarkers. Recently, brain-enriched miRNAs regulating vital neurological functions have been proposed as potent biomarkers for therapeutic strategies. Therefore, the present study is aimed to identify the brain-enriched miR-218-5p and miR-320-5p in the serum of the Chinese depressed PD patients (n = 51) than healthy controls (n = 51) to identify their potency as biomarkers. For this purpose, depressive PD patients were recruited based on HAMA and HAMD scores and miR-218-5p and miR-320-5p and IL-6, and S100B levels were analyzed using real-time PCR (qRT-PCR) and ELISA assay, respectively. In silico analysis was performed to identify key biological pathways and hub genes involved in the psychopathology of depression in PD. Here, we found significantly downregulated miR-218-5p and miR-320-5p following higher levels of IL-6 and S100B in depressed PD patients than in control (p < 0.05). The correlation analysis revealed that both miRNAs were negatively correlated with HAMA and HAMD, and IL-6 scores, along with a positive correlation with PD duration and LEDD medication. ROC analysis showed AUC above 75% in both miRNAs in depressed PD patients, and in silico analysis revealed that both miRNA's targets regulate key neurological pathways such as axon guidance, dopaminergic synapse, and circadian rhythm. Additional analysis revealed PIK3R1, ATRX, BM1, PCDHA10, XRCC5, PPP1CB, MLLT3, CBL, PCDHA4, PLCG1, YWHAZ, CDH2, AGO3, PCDHA3, and PCDHA11 as hub-genes in PPI network. In summary, our findings show that miR-218-5p and miR-320-5p can be utilized as future biomarkers for depression in PD patients, which may aid in the early diagnosis and treatment of Parkinson's disease.


Combined whole tumor cell and monophosphoryl lipid A vaccine improved by encapsulation in murine colorectal cancer.
Whole autologous colon cancer vaccines in combination with various adjuvants have been used in both animals and humans. At this writing, vaccine regimens have been initiated in humans 3 to 6 weeks postoperatively. This delay between tumor resection and vaccination gives surviving tumor cells an opportunity to establish themselves. Vaccine administered either preoperatively or immediately after surgery, in theory, should be more effective. However, surgery-related immunosuppression may diminish the effectiveness of pre-operative or early postoperative vaccines. This problem may be overcome by limiting postoperative immunosuppression via the use of minimally invasive methods. Alternatively, the impact of the vaccine may be improved by encapsulating the vaccine, plus adjuvant, which in theory, should extend exposure time. Encapsulation of cancer vaccines in polysaccharide particles has not yet been studied. The goal of this study was to determine whether vaccine encapsulation, preoperative vaccination, and early postoperative vaccination affected the tumor burden. In addition, laparotomy and carbon dioxide insufflation were compared. Vaccine was prepared from ultraviolet-irradiated C26 colon cancer cells in combination with monophosphoryl lipid A, either in suspension or entrapped in alginate beads. The C26 cell line and syngeneic BALB/c mice were used for all the studies. Tumor volumes were determined after excision of the tumors 2 weeks after inoculation in these studies. Encapsulated vaccine was more effective than the standard liquid vaccine. Significantly smaller tumors were noted in mice receiving encapsulated vaccine than in either the control group (p <0.01) or the liquid vaccine group (p <0.05). The use of a preoperative encapsulated vaccine was associated with significantly smaller tumors after laparotomy, pneumoperitoneum, or anesthesia alone when the tumors were established immediately after surgery. With an already established tumor, encapsulated vaccine, when given in the early postoperative period to mice that had undergone laparotomy or anesthesia alone was associated with significantly smaller tumors that those found in control animals. The incorporation of a whole-cell vaccine and monophosphoryl lipid A into alginate beads increases the efficacy of pre-operative and early postoperative tumor vaccines in the setting of both laparotomy and Carbon dioxide pneumoperitoneum. The use of perioperative vaccines may prove to be an effective way to immunize patients with cancer undergoing surgery.


Application of gastrointestinal simulation for extensions for biowaivers of highly permeable compounds.
The goal of this study was to apply gastrointestinal simulation technology and integration of physiological parameters to predict biopharmaceutical drug classification. GastroPlus was used with experimentally determined physicochemical and pharmacokinetic drug properties to simulate the absorption of several weak acid and weak base BCS class II compounds. Simulation of oral drug absorption given physicochemical drug properties and physicochemical parameters will aid justification of biowaivers for selected BCS class II compounds.


Intermediate stimulation frequencies for language mapping using Stereo-EEG.
Identification of eloquent cortices is a prerequisite for the surgical plan but may be challenging, in particular for language areas (LAs), considering the complexity of language function and organization. Electrical intracerebral stimulations (ES) during Stereo-electroencephalography are an essential tool in the localization of LAs and high frequency ES (HFS, 50 Hz) are current gold standard. Low frequencies (1 Hz) are not effective. We aim to investigate different ES frequencies for establishing their utility in localizing LAs. We implemented an observational and prospective study evaluating frequencies lower than 50 and higher than 1 Hz; indicated as "intermediate" frequencies (IFS) performed at 6, 9 and 12 Hz and lasting 15 seconds. We included ten patients and carried out a standardized protocol comparing IFS to HFS. Eighty-six ES were carried out in LAs, positive for a language interference in 61.6% without noteworthy difference between IFS and HFS. Among these, 53.3% IFS vs 21.7% HFS yielded no after-discharge. IFS were similarly effective as HFS, with lower incidence of ADs. Their longer duration facilitated more accurate clinical testing. Our results are promising, suggesting that IFS can be useful in the study of LAs.


Cell-specific expression of runt-related transcription factor 2 contributes to pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with limited therapeutic options and unknown etiology. IPF is characterized by epithelial cell injury, impaired cellular crosstalk between epithelial cells and fibroblasts, and the formation of fibroblast foci with increased extracellular matrix deposition (ECM). We investigated the role of runt-related transcription factor 2 (RUNX2), a master regulator of bone development that has been linked to profibrotic signaling. RUNX2 expression was up-regulated in lung homogenates from patients with IPF and in experimental bleomycin-induced lung fibrosis. The RUNX2 level correlated with disease severity as measured by decreased diffusing capacity and increased levels of the IPF biomarker, matrix metalloproteinase 7. Nuclear RUNX2 was observed in prosurfactant protein C-positive hyperplastic epithelial cells and was rarely found in myofibroblasts. We discovered an up-regulation of RUNX2 in fibrotic alveolar epithelial type II (ATII) cells as well as an increase of RUNX2-negative fibroblasts in experimental and human pulmonary fibrosis. Functionally, small interfering RNA-mediated RUNX2 knockdown decreased profibrotic ATII cell function, such as proliferation and migration, whereas fibroblasts displayed activation markers and increased ECM expression after RUNX2 knockdown. This study reveals that RUNX2 is differentially expressed in ATII cells vs. fibroblasts in lung fibrosis, which contributes to profibrotic cell function. Cell-specific targeting of RUNX2 pathways may represent a therapeutic approach for IPF.-Mümmler, C., Burgy, O., Hermann, S., Mutze, K., Günther, A., Königshoff, M. Cell-specific expression of runt-related transcription factor 2 contributes to pulmonary fibrosis.


Item-Specific Factors in IRTree Models: When They Matter and When They Don't.
Lyu et al. (Psychometrika, 2023) demonstrated that item-specific factors can cause spurious effects on the structural parameters of IRTree models for multiple nested response processes per item. Here, we discuss some boundary conditions and argue that person selection effects on item parameters are not unique to item-specific factors and that the effects presented by Lyu et al. (Psychometrika, 2023) may not generalize to the family of IRTree models as a whole. We conclude with the recommendation that IRTree model specification should be guided by theoretical considerations, rather than driven by data, in order to avoid misinterpretations of parameter differences.


Implicit and explicit memory for emotion-congruent information in clinical depression and anxiety.
Implicit and explicit memory biases were assessed in clinically depressed (n = 19), clinically anxious (n = 17), and normal control (n = 18) Ss. The implicit memory test was a primed lexical decision task, with anxiety- and depression-relevant words, and suprathreshold and subthreshold primes. The explicit memory test was incidental free recall of self-referenced words. The depressed group showed greater suprathreshold and subthreshold priming effects for depression words, and recalled more depression words, than the other two groups. These results suggest that clinical depression, but not clinical anxiety, is associated with mood-congruent biases in both automatic and strategic memory processes.


Mitotic recombination can explain the apparent polyclonal origin of some tumors.
Although most human tumors appear to be monoclonal in origin, a few express two G6PD types; on this basis they have been thought to be polyclonal in origin and exceptions to the general rule of monoclonality. In light of the recent discovery that mitotic recombination can cause a shift from genetic heterozygosity to homozygosity in tumor cells, we suggest that such a mechanism can also explain the occasional occurrence of two G6PD types in a monoclonal tumor.


Small intestinal morphology and epithelial cell kinetics in lamb rotavirus infections.
Morphologic changes in the small intestine of rotavirus-infected gnotobiotic lambs were investigated by measurement of villi and crypts in histologic sections of jejunum, midgut, and posterior ileum. In midgut, villus atrophy developed within 12 hr of infection and was apparent until 72 hr after infection. Crypt hypertrophy was evident from 42 hr after infection until the end of the observation period (6 days after infection). Changes in posterior ileum were similar in extent, but jejunal changes were much less marked. The relatively mild effect in the jejunum is in accord with reports from other species, and provides a basis for questioning the assumption that human rotavirus affects mainly the foregut. Studies of epithelial cell kinetics were made on midgut using a microdissection and metaphase accumulation technique on sequential samples from anesthetized lambs. An increase in the cell production rate per crypt per hour from the overall control level of 5.8 was detected by 48 hr after infection. The maximum level of 21.2 was reached 8 days after infection, and this had returned to near normal by 15 days after infection. This large and sustained increase in crypt cell production probably underlies other previously described functional abnormalities.


An efficient and highly selective deprotecting method for beta-(trimethylsilyl)ethoxymethyl ethers.
A series of beta-(trimethylsilyl)ethoxymethyl ethers were hydrolyzed to their corresponding alcohols in high yields by using a catalytic amount of CBr4 (15%) in MeOH under refluxing reaction conditions. The chemoselective deprotection between trialkylsilyl and beta-(trimethylsilyl)ethoxymethyl-protected alcohols can be achieved by using an alcohol with steric hindrance such as iPrOH. The selectivity also can be achieved in the CBr4/MeOH reaction mixture under ultrasonic reaction conditions.


NC-1900, an arginine-vasopressin analogue, ameliorates social behavior deficits and hyperlocomotion in MK-801-treated rats: therapeutic implications for schizophrenia.
We previously reported that chronic administration of N-methyl-D-aspartate (NMDA) antagonists reduced the density of vasopressin V1a receptors in several brain regions in rats that demonstrated social interaction deficits and increased locomotor activity. These observations indicate the ability of arginine-vasopressin (AVP), or its analogues, to modulate behavioral abnormalities associated with blockade of NMDA receptors. The present study was performed to investigate the effect of NC-1900, an AVP analogue, on social behavior and locomotor activity in rats treated with MK-801, a non-competitive NMDA receptor antagonist. Male Wistar rats were administered MK-801 (0.13 mg/kg/day ip) or saline for 14 days. Social behavior and locomotor activity were measured 45 min after the injection of NC-1900 (10 ng/kg sc) or saline together with the last MK-801 or vehicle administration. Social interaction was quantified by an automated video-tracking system, and stereotyped behavior and ataxia were manually measured. Acute administration of NC-1900 partially reversed MK-801-induced hyperlocomotion and deficits in social interaction, while NC-1900 itself did not affect these behavioral measures in animals chronically treated with vehicle saline. These results suggest that the central AVP system may interact with glutamatergic and dopaminergic transmissions, and indicate potential therapeutic effects of AVP analogues on positive and negative symptoms of schizophrenia.


Multiplex microsphere immuno-detection of potato virus Y, X and PLRV.
To monitor seed potatoes for potato virus X, Y and PLRV, a multiplex microsphere immunoassay (MIA) was developed based on the Luminex xMAP technology, as an alternative to ELISA. The xMAP technology allowed detection of a number of antigens simultaneously whereas ELISA only allowed simplex detection of antigens. The use of paramagnetic beads in the MIA procedure allowed efficient removal of excess sample compounds and reagents. This resulted in lower background values and a higher specificity than a non-wash MIA procedure using conventional beads. In a simplex MIA detection, levels for PVY and PLRV in potato leaf extracts were 10 times lower than ELISA but for PVX 10 timers higher, whereas the specificity was similar. Results of a multiplex assay performed on viruses added to potato leaf extracts were largely similar to those of ELISA for individual viruses. Results of samples infected naturally with PVX, PVY or PLRV were comparable with ELISA.


Decision-To-Scope Score: A novel tool with excellent accuracy in predicting foreign bodies in the esophagus.
Foreign body (FB) ingestion is a common indication for urgent esophagogastroduodenoscopy (EGD). Nevertheless, most pass spontaneously through the gastrointestinal (GI) tract. Differently from GI bleeding, there is no validated score aiming to identify "low-risk" patients in suspected FB ingestion. We aimed to create a score able to discriminate patients who are candidates to emergent EGD in this scenario. Retrospective study of consecutive patients admitted for suspected FB in the upper GI tract between 2016 and 2021. The evaluated outcome was endoscopic confirmation of FB in the esophagus. Variables significantly associated with the outcome on multivariate analysis were computed into a score predicting endoscopic confirmation. We included 228 patients. From these, 97 (42.5%) had a confirmed FB in EGD. Time since ingestion <6 h (OR = 4.0; P = 0.042), absence of any meal after FB ingestion (OR = 7.1; P = 0.005), dysphagia (OR = 11.8; P < 0.001), odynophagia (OR = 4.6; P = 0.004), and drooling (OR = 15.1; P < 0.001) were independent predictors of confirmed FB. These variables were used to compute a FB predicting score-the Decision-To-Scope (DTS) Score: time since ingestion <6 h (+1 point), absence of meals (+2 points), dysphagia (+3 points), odynophagia (+1 point), and drooling (+4 points). DTS-Score had excellent accuracy to predict the outcome (AUC = 0.953; 95%CI = 0.928-0.977; P < 0.001). The optimal cutoff to identify low-risk patients was a score ≤5 (sensitivity 85.0% and specificity 94.7%). More than half of the suspected FB were not confirmed by EGD. The DTS-Score presented excellent accuracy at stratifying patients' risk and may contribute to the decision to perform emergent EGD in suspected FB ingestion.


CXXC5 plays a role as a transcription activator for myelin genes on oligodendrocyte differentiation.
Myelination in corpus callosum plays important role for normal brain functions by transferring neurological information between various brain regions. However, the factors controlling expression of myelin genes in myelination are poorly understood. Here, CXXC5, a recently identified protein with CXXC-type zinc finger DNA binding motif, was characterized as a transcriptional activator of major myelin genes. We identified expression of CXXC5 expression was increased by Wnt/β-catenin signaling. CXXC5 specifically expressed in the white matter induced expression of myelin genes through the direct binding of CXXC DNA-binding motif of CXXC5 on the MBP promoter. During the differentiation of neural stem cells (NSCs) of CXXC5(-/-) mice, the expressions of myelin genes were simultaneously reduced. The CXXC5(-/-) mice exhibited severely reduction of myelin genes expression in corpus callosum as well as abnormalities in myelin structure. The disrupted structural integrity of myelin in the CXXC5(-/-) mice resulted in reduced electrical conduction amplitudes at corpus callosum. These findings indicate that the regulation of myelin genes expression by CXXC5 is important for forming myelin structure involved with axonal electrical signal transfer in the corpus callosum.


Individual differences in smoking-related cue reactivity in smokers: an eye-tracking and fMRI study.
Measures of cue reactivity provide a means of studying and understanding addictive behavior. We wanted to examine the relationship between different cue reactivity measures, such as attentional bias and subjective craving, and functional brain responses toward smoking-related cues in smokers. We used eye-tracking measurements, a questionnaire for smoking urges-brief and functional magnetic resonance imaging to assess the responses to smoking-related and neutral visual cues from 25 male smokers after 36 h of smoking abstinence. Regression analyses were conducted to determine the correlation between cue-evoked brain responses and the attentional bias to smoking-related cues. The eye gaze dwell time percentage was longer in response to smoking-related cues than neutral cues, indicating significant differences in attentional bias towards smoking-related cues. The attentional bias to smoking-related cues correlated with subjective craving ratings (r=0.660, p<0.001). The dorsolateral prefrontal cortex, the putamen, the posterior cingulate cortex and the primary motor cortex were associated with the attentional bias to smoking-related cues, whereas the orbitofrontal cortex, the insula and the superior temporal gyrus were associated with smoking-related cue-induced craving and smoking urges. These results suggest that attentional mechanisms in combination with motivational and reward-related mechanisms play a role in smoking-related cue reactivity. We confirmed a positive correlation between different smoking-related cue reactivities, such as attentional bias and subjective craving, and functional brain responses in various individuals. Further studies in this field might contribute to a better individualized understanding of addictive behavior.