Safety and efficacy of the combination of the glucagon-like peptide-1 receptor agonist liraglutide with an oral antidiabetic drug in Japanese patients with type 2 diabetes: Post-hoc analysis of a randomized, 52-week, open-label, parallel-group trial.
The aim of the present post-hoc analysis was to investigate the safety and efficacy of liraglutide in combination with one oral antidiabetic drug (OAD) across different OAD classes. This was a post-hoc analysis using data from a 52-week, open-label, parallel-group trial, in which patients with type 2 diabetes inadequately controlled with a single OAD (α-glucosidase inhibitor, glinide, metformin or thiazolidinedione) were randomized to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group) or pretrial OAD in combination with an additional OAD (additional OAD group). The primary outcome investigated in this post-hoc analysis was the incidence of adverse events. The proportions of patients experiencing adverse events across the different groups of pretrial OADs were comparable between liraglutide and additional OAD (α-glucosidase inhibitor 74.6 vs 70.0%; glinide 93.1 vs 87.1%; metformin 91.8 vs 87.1%; thiazolidinedione 86.2 vs 96.4%, respectively). Minor hypoglycemia was infrequent (seven episodes in two patients randomized to liraglutide, and two episodes in two patients randomized to additional OAD). The mean reduction in glycated hemoglobin appeared greater with liraglutide therapy, with the estimated mean treatment difference (95% confidence interval [CI]) for liraglutide vs additional OAD ranging from -0.14%, 95% CI: -0.48 to 0.21 (-1.5 mmol/mol, 95 CI: -5.2 to 2.3) to -0.44%, 95% CI:-0.79 to -0.09 (-4.8 mmol/mol, 95% CI: -8.6 to -1.0). The present analysis suggests that Japanese patients on OAD monotherapy might benefit from a greater improvement in glycemic control, without impacting tolerability, by combining their OAD with liraglutide rather than another OAD, regardless of which OAD monotherapy they are receiving.


Sources of energy for the brain and physical dependence on ethanol.
This paper describes a proposed biochemical mechanism to account for physical dependence on ethanol. Long-term exposure to a continuous and plentiful supply of ethanol-derived hydrogens in NADH and ethanol-derived acetyl-CoA (AcCoA) may lead to a decreased rate of production of endogenous hydrogens in NADH and endogenous AcCoA in compensation. It is proposed that physical dependence on ethanol occurs when ketolytic- and glycolytic-based NADH and AcCoA synthetic rates fall below the rate of utilization by the brain; the brain then "depends" on alcohol-derived NADH and AcCoA for normal function.


Raising the LUMO level of fullerene derivatives alleviates the output voltage loss in tin halide perovskite solar cells.
Two fullerene derivatives C60-MP and C60-ETPA were designed and synthesized for tin-halide perovskite solar cells. The introduction of an electron-withdrawing group and an alkyl chain reduced the electron affinity, resulting in a shallower lowest unoccupied molecular orbital (LUMO) energy level than that of common phenyl-C61-butyric acid methyl ester (PC61BM). Moreover, the smaller energy level offset provided efficient carrier transport and suppressed charge recombination. As a result, the devices with C60-ETPA achieved an open-circuit voltage of 0.76 V and a power conversion efficiency of over 10%, which were substantially higher than 0.63 V and 8.25% for the control devices with PC61BM, respectively.


Interaction between SO2 and cold-induced bronchospasm in anesthetized rabbits.
In anesthetized, paralyzed and artificially ventilated rabbits, reflex changes in lung resistance induced by cooling the inspired air from 38 to 15 degrees C were studied before and after 45 min periods of SO2 exposure at two different concentrations (0.5 or 5 ppm). Both concentrations of SO2 induced significant increase in RL in intact animals (+16% and +50%, respectively). The effect of 5 ppm SO2 persisted after vagotomy. The cold-induced bronchospasm was halved after exposure to 0.5 ppm SO2 and was no longer significant after exposure to 5 ppm SO2. In both cases, RL recovered to control values 40 min after the end of SO2 exposure and then, the magnitude of cold-induced bronchospasm also recovered. The reflex bronchoconstrictor response to phenyldiguanide (PDG) i.v. disappeared after exposure to 5 ppm SO2. However, the bronchomotor response to histamine i.v., which involved both reflex and direct actions on airway smooth muscle, was not altered. These results show that (1) prolonged increase in RL measured after SO2 exposure does not result from a vagal reflex; (2) the cold-induced bronchospasm, as well as the bronchomotor response to PDG, are reduced or suppressed during the period where the effect of SO2 persisted. This suggests that 45 min exposure to SO2 induces transient alterations in tracheobronchial wall, which reduce the accessibility to nervous receptors in the airways.


Histidine Nτ-methylation identified as a new posttranslational modification in histone H2A at His-82 and H3 at His-39.
Histone posttranslational modifications play critical roles in a variety of eukaryotic cellular processes. In particular, methylation at lysine and arginine residues is an epigenetic mark that determines the chromatin state. In addition, histone "histidine" methylation was initially reported over 50 years ago; however, further studies in this area were not conducted, leaving a gap in our understanding. Here, we aimed to investigate the occurrence of histidine methylation in histone proteins using highly sensitive mass spectrometry. We found that acid hydrolysates of whole histone fraction from calf thymus contained Nτ-methylhistidine, but not Nπ-methylhistidine. Both core and linker histones carried a Nτ-methylhistidine modification, and methylation levels were relatively high in histone H3. Furthermore, through MALDI-TOF MS, we identified two histidine methylation sites at His-82 in the structured globular domain of histone H2A and His-39 in the N-terminal tail of histones H3. Importantly, these histidine methylation signals were also detected in histones purified from a human cell line HEK293T. Moreover, we revealed the overall methylation status of histone H3, suggesting that methylation is enriched primarily at lysine residues and to a lesser extent at arginine and histidine residues. Thus, our findings established histidine Nτ-methylation as a new histone modification, which may serve as a chemical flag that mediates the epigenetic mark of adjacent residues of the N-terminal tail and the conformational properties of the globular domain.


Expression of membrane and nuclear melatonin receptors in mouse peripheral organs.
Previous studies have shown that melatonin acts through specific receptors, including MT(1) and MT(2) membrane receptors as well as a nuclear receptor belonging to the orphan nuclear receptor family. Therefore, the goal of this study was to determine whether melatonin receptors mRNA is expressed in mouse peripheral tissues. To study the different receptors subtype expression, we have used a reverse-transcription polymerase chain reaction (RT-PCR) procedure followed by Southern hybridization with specific digoxigenin-labeled probes. RT-PCR studies revealed the presence of both MT(1) membrane receptors and ROR(alpha)1 nuclear receptors in all the peripheral tissues examined (brain, heart, lung, liver and kidney). Moreover, the expression of ROR(alpha)1 nuclear receptors was also demonstrated by Western-blot. In contrast, expression of MT(2) membrane receptors was only observed in brain and lung. These results suggest that melatonin, acting through its different subtypes receptors, plays a role in the neuroendocrine regulation of peripheral tissues function.


Release of endogenous GABA from the cat red nucleus slices.
The release of endogenous gamma-aminobutyric acid (GABA) from the cat red nucleus was studied in a slice preparation. Potassium-induced depolarization caused a release of GABA in a calcium-dependent manner. The release of GABA was also induced by veratrine and blocked by tetrodotoxin. The demonstration of release satisfies one of the important criteria for identification of GABA as the inhibitory neurotransmitter.


Return to Sports After ACL Augmentation With Anterolateral Reconstruction (ALR) Harvesting Gracilis Only Compared With ACL Reconstruction With ALR Harvesting Both Hamstring Tendons.
Anterior cruciate ligament (ACL) repair (ACL-Rp) is known to be a valuable alternative to ACL reconstruction (ACL-Rc) in selected indications. The majority of the ACL-Rp techniques recommend the use of a synthetic brace. The use of the gracilis allows both a biological internal brace and anterolateral ligament reconstruction (ALR). The primary objective was to compare the early ability to return to sports between patients who underwent ACL-Rp using a gracilis autograft as an internal brace augmentation with ALR and patients who underwent the conventional ACL-Rc with ALR technique sacrificing both the gracilis and the semitendinosus. The secondary objective was to compare the failure rate, clinical scores, and return to sports at a minimum follow-up of 2 years. Cohort study; Level of evidence, 3. A retrospective analysis was undertaken. A total of 49 patients who underwent ACL-Rp with ALR between December 2018 and May 2019 were propensity matched at a 1:1 ratio to those who underwent ACL-Rc with ALR during the same period. The decision to perform ACL-Rp with ALR was based on preoperative selection and intraoperative arthroscopic findings: proximal avulsion tear, partial ACL tear, low- to midlevel sports participation, and good tissue quality. The ability to return to sports was assessed using isokinetic tests and the Knee Santy Athletic Return to Sport test functional test at 6 months postoperatively. At the final follow-up, knee laxity parameters, return to sports, and clinical outcome (Lysholm score, Tegner Activity Scale score, International Knee Documentation Committee score, Knee injury and Osteoarthritis Outcome Score, and Anterior Cruciate Ligament-Return to Sport after Injury score) were recorded. The ACL-Rp group had significantly less hamstring strength deficit when compared with their counterparts who underwent ACL-Rc (0.2% vs 10.2% in concentric, P < .001; 2.5% vs 14% in eccentric, P < .001). The mean Knee Santy Athletic Return to Sport test score was significantly higher in the ACL-Rc group (69.7% ± 16.6% [range, 19%-100%] vs 61% ± 16.8% [range, 19%-100%]; P = .001). In the ACL-Rp group, 61% (30/49) of the patients were authorized to return to pivot sports versus 41% (20/49) in the ACL-Rc group (P = .04). At a mean final follow-up of 31.4 ± 3.5 months, no significant differences were demonstrated between groups with respect to clinical scores and knee laxity parameters. There was a trend for a higher failure rate in the ACL-Rp group without any significance (ACL-Rp: 6.1% [3/49] vs ACL-Rc: 0%; P = .08). At 6 months after operation, harvesting only the gracilis with this ACL-Rp and augmentation with ALR technique was linked to a better early ability to return to sports compared with the ACL-Rc with ALR technique harvesting both the gracilis and semitendinosus. This technique had a limited effect on early flexion strength and provided a satisfactory rerupture rate.


Repetitive transcranial magnetic stimulation alleviates glial activation through suppressing HMGB1/TLR4 pathway in a rat model of Parkinson's disease.
Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to be effective in Parkinson's disease (PD), but whether rTMS treatment has a relieving effect on neuroinflammation remains to be investigated. In this article, we explored the effects of rTMS on forelimb use asymmetry and neuroinflammation-related mechanisms in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Rats in the 6-OHDA+rTMS group received 10 Hz rTMS daily for 4 weeks. Behavioral tests (the cylinder test) were performed at the 3rd and 7th weeks after the operation. Astrocyte and microglia activation and protein levels of tyrosine hydroxylase(TH), high-mobility group box 1(HMGB1) and toll-like receptors 4(TLR4) were investigated by immunohistochemistry and Western blot analyses, respectively. After 4 weeks of treatment, forelimb use asymmetry was ameliorated in the 6-OHDA+rTMS group. Consistent with the behavioral tests, rTMS increased TH in the substantia nigra (SN) and the striatum of PD rats. High glial activation and HMGB1/TLR4 expression in the SN and the striatum were observed in the 6-OHDA group, while rTMS alleviated these changes. This study showed that rTMS might be a promising method for alleviating neuroinflammation in PD rat models, and the effects might be mediated through the downregulation of the HMGB1/TLR4 pathway.


Determination of plasma non-esterified fatty acids and triglyceride fatty acids by gas chromatography of their methyl esters after isolation by column chromatography on silica gel.
Non-esterified fatty acids (NEFA) and triglycerides were isolated from human plasma by column chromatography on silica gel. Eight principal fatty acids of each of these lipid classes were determined by gas chromatography of their methyl ester derivatives and quantified relative to multipoint standard curves. Within-day relative standard deviations for plasma non-esterified fatty acid and triglyceride fatty acid determinations were 2.4 and 3.2%, respectively. Day-to-day relative standard deviations for plasma non-esterified fatty acid and triglyceride fatty acid determinations were 1.4 and 1.1%, respectively. The total plasma concentration and the relative proportions of the eight non-esterified fatty acids determined by this method were significantly different from results obtained according to two generally accepted methods for direct plasma non-esterified fatty acid determination without a specific isolation step. These comparisons suggested that considerable fatty acid ester lipid hydrolysis occurred during these direct determination procedures, and that this hydrolysis resulted in 3-fold overestimation of plasma NEFA content by those methods. Measured levels of arachidonic acid are substantially overestimated by these direct determination methods in which non-esterified fatty acids are not isolated before derivatization.


Comparison of immunological methods for diagnosis of pneumococcal pneumonia in biological fluids.
Five immunological tests were evaluated for their ability to detect Streptococcus pneumoniae antigen in serum and urine simultaneously as a means of rapid diagnosis in 40 patients with bacteremic or non-bacteremic pneumococcal pneumonia or pneumonia with other etiologies. Serum and urine were screened in parallel with counterimmunoelectrophoresis (CIE), two commercial latex agglutination kits - the Slidex pneumokit (LA-SPK) and the Bactigen Streptococcus pneumoniae kit (LA-Bac) - the coagglutination Phadebact Pneumococcus test (CoA) and a newly developed enzyme-linked immunosorbent assay (ELISA) containing the immunoglobulin G fraction from rabbit pneumococcal antiserum. The detection rate for accumulated serum in bacteremic patients was 18% for LA-Bac, 24% for CIE, 47% for LA-SPK and CoA and 76% for ELISA, whereas antigenuria was present in only 29% for LA-SPK, 24% for CIE, 19% for CoA, 14% for LA-Bac and 5% for ELISA. Detection by ELISA of pneumococcal antigen in severely ill patients can predict bacteremia and rapidly confirm the diagnosis of pneumococcal pneumonia if sputum and results of blood cultures are not available.


Treatment of ectopic pregnancy by local injection of hypertonic glucose: a randomized trial comparing administration guided by transvaginal ultrasound or laparoscopy.
To study local treatment of ectopic pregnancy by injection of hyperosmolar (50%) glucose, guided either by transvaginal ultrasound or by laparoscopy. Eighty women were randomized, 39 into the sonography and 41 into the laparoscopy group. Criteria for inclusion were 1) ectopic pregnancy < or = 4 cm seen by transvaginal ultrasound, 2) hCG < or = 3000 IU/l, and 3) little or no intraabdominal bleeding. In the sonography group, patients were treated by one skilled ultrasound investigator, whereas injections by laparoscopy were performed by several colleagues. The former group were offered a second glucose injection if hCG levels were rising. Those successfully treated were offered hysterosalpingography (HSG) for evaluation of tubal patency. Twenty-nine (74.4%) women were successfully treated in the sonography group by one single injection, compared to 21 (51.2%) in the laparoscopy group. Eight women in the sonography group received a second glucose injection because of a rising hCG, increasing the success rate in this group to 82.1% (32 of 39 women). Six patients in the laparoscopy group were not injected due to technical difficulties during the operation, and the success rate for those injected were 60% (21 of 35 women). The overall success rate was 66.3%. Of the 28 women investigated by HSG, both tubes were normal in 19 (67.8%), and in 25 patients (89.3%) the treated tube was open. Local injection of hyperosmolar glucose guided by transvaginal ultrasound by one skilled investigator is an effective treatment for ectopic pregnancy. Most women preserve tubal patency after treatment.


GOLPH3 regulates the migration and invasion of glioma cells though RhoA.
Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development of several human cancers. However, the biological significance of GOLPH3 in glioma progression remains largely unknown. In this study, we report, for the first time, that downregulation of GOLPH3 led to clear reductions in glioma cell migration and invasion. In addition, downregulation of GOLPH3 inhibited the expression of the small GTPase RhoA as well as cytoskeletal reorganization, which are both required for glioma cell migration. Furthermore, we found that the observed reductions in glioma cell migration and RhoA level could be rescued by RhoA overexpression. Taken together, these results show that GOLPH3 contributes to the motility of glioma cells by regulating the expression of RhoA.


Japanese sake yeast supplementation improves the quality of sleep: a double-blind randomised controlled clinical trial.
Activation of adenosine A2a receptors in cerebral neurons induces sleep in various mammals. It was previously found that Japanese sake yeast enriched in adenosine analogues activates A2a receptors in vitro and induces sleep in mice. Here it is reported that sake yeast activated A2a receptors in a cultured human cell line and improved human sleep quality in a clinical trial. Sake yeast activated A2a receptors in HEK cells in a dose-dependent manner with an EC50 of 40 μg mL(-1), and the activation was attenuated almost completely by the A2a receptor antagonist ZM241385 with an IC50 of 73 nm. In a double-blind placebo-controlled crossover clinical study, 68 healthy participants ingested tablets containing either 500 mg of sake yeast powder or a placebo (cellulose) 1 h before sleep for 4 days. Electroencephalograms were recorded during sleep at home with a portable device for 4 week days. Electroencephalogram analyses revealed that sake yeast supplementation significantly (P = 0.03) increased delta power during the first cycle of slow-wave sleep by 110%, without changing other sleep parameters. Sake yeast supplementation also significantly increased growth hormone secretion in the urine on awakening by 137% from 3.17 ± 0.41 (placebo) to 4.33 ± 0.62 (sake yeast) pg mg(-1) creatinine (P = 0.03). Subjective sleepiness (P = 0.02) and fatigue (P = 0.06) in the morning were improved by sake yeast. Given these benefits and the absence of adverse effects during the study period, it was concluded that sake yeast supplementation is an effective and safe way to support daily high-quality, deep sleep.


Critical path activities in clinical trial setup and conduct: How to avoid bottlenecks and accelerate clinical trials.
Most clinical trials are delayed due to scientific and/or operational challenges. Any effort to minimize delays can generate value for patients and sponsors. This article reviews critical path process steps commonly identified by practitioners, such as during protocol development, site contracting, or patient recruitment. Commonly considered measures, such as adding more trial sites or countries, were contrasted with less frequented measures, such as evidence-based feasibility or real-world evidence analysis, to help validate assumptions before clinical trial initiation. In a broad analysis, we integrated a literature review with a practitioner survey into a framework to help decision makers on the most critical process steps when setting up or conducting clinical trials in order to bring critical treatments to patients faster.


The possible role of Mena protein and its splicing-derived variants in embryogenesis, carcinogenesis, and tumor invasion: a systematic review of the literature.
The Ena/VASP (enabled/vasodilator stimulated phosphoprotein) family includes the binding actin proteins such as mammalian Ena (Mena), VASP, and Ena-VASP-like. It is known that the perturbation of actin cycle could determine alteration in the mobility of cells and in consequence of organogenesis. Few recent studies have revealed that Mena protein could play a role in breast or pancreatic carcinogenesis. Based on our researches, we observed that the intensity of Mena expression increased from premalignant to malignant lesions in some organs such as large bowel, stomach, cervix, and salivary glands. These findings prove that Mena could be a marker of premalignant epithelial lesions. In premalignant lesions, it could be helpful to define more accurately the risk for malignant transformation. In malignant tumors, correlation of expression of its splice variants could indicate metastatic behavior. In conclusion, we consider that it is necessary to analyze the expression of Mena splice variants in a higher number of cases, in different epithelial lesions, and also in experimental studies to define its exact role in carcinogenesis and also its possible prognostic and predictive values.


Tumor Metabolism Is Affected by Obesity in Preclinical Models of Triple-Negative Breast Cancer.
Obesity is characterized by an excessive fat mass accumulation associated with multiple disorders, including impaired glucose homeostasis, altered adipokine levels, and hyperlipidemia. Despite clear associations between tumor progression and obesity, the effects of these disorders on tumor metabolism remain largely unknown. Thus, we studied the metabolic differences between tumors of obese and lean mice in murine models of triple-negative breast cancer (E0771 and PY8819). For this purpose, a real-time hyperpolarized 1-13C-pyruvate-to-lactate conversion was studied before and after glucose administration in fasting mice. This work was completed by U-13C glucose tracing experiments using nuclear magnetic resonance (NMR) spectroscopy, as well as mass spectrometry (MS). Ex vivo analyses included immunostainings of major lipid, glucose, and monocarboxylic acids transporters. On the one hand, we discovered that tumors of obese mice yield higher lactate/pyruvate ratios after glucose administration. On the other hand, we found that the same tumors produce higher levels of lactate and alanine from glucose than tumors from lean mice, while no differences on the expression of key transporters associated with glycolysis (i.e., GLUT1, MCT1, MCT4) have been observed. In conclusion, our data suggests that breast tumor metabolism is regulated by the host's physiological status, such as obesity and diabetes.


Tolerability and efficacy of perampanel in children with refractory epilepsy.
There are few reports on the tolerability and efficacy of perampanel, a new antiepileptic drug with a novel mechanism of action, in children and adolescents. We aimed to describe our experience with perampanel add-on and mono-therapy in children with refractory epilepsy. Computerized medical records of children treated with perampanel in the paediatric neurology clinic from December 2012 to October 2015 were reviewed. Twenty-four children treated with perampanel (15 females, 9 males) aged 1 year 6 months to 17 years (mean 10y, standard deviation [SD] 4y 5mo) were identified. Adverse events were more common in children aged 12 years or older (89%) compared to younger children (53%), and were mainly behavioural. Ten (42%) children had 50 per cent or higher seizure reduction, two (8%) children had 33 per cent seizure reduction, and seizures were less severe in one (4%) child. Perampanel was discontinued in 13 (54%) children mostly due to adverse events. The mean duration of follow-up in the remaining 11 children was 8.1 months (SD 5.2) (range 1.3-17mo). Perampanel is associated with a relatively high rate of behavioural adverse events mostly in adolescents with refractory epilepsy.


Biomechanical modeling of invasive breast carcinoma under a dynamic change in cell phenotype: collective migration of large groups of cells.
According to recent studies, cancer is an evolving complex ecosystem. It means that tumor cells are well differentiated and involved in heterotypic interactions with their microenvironment competing for available resources to proliferate and survive. In this paper, we propose a chemo-mechanical model for the growth of specific subtypes of an invasive breast carcinoma. The model suggests that a carcinoma is a heterogeneous entity comprising cells of different phenotypes, which perform different functions in a tumor. Every cell is represented by an elastic polygon changing its form and size under pressure from the tissue. The mechanical model is based on the elastic potential energy of the tissue including the effects of contractile forces within the cell perimeter and the elastic resistance to stretching or compressing the cell with respect to the reference area. A tissue can evolve via mechanisms of cell division and intercalation. The phenotype of each cell is determined by its environment and can dynamically change via an epithelial-mesenchymal transition and vice versa. The phenotype defines the cell adhesion to the adjacent tissue and the ability to divide. In this part, we focus on the forms of collective migration of large groups of cells. Numerical simulations show the different architectural subtypes of invasive carcinoma. For each communication, we examine the dynamics of the cell population and evaluate the complexity of the pattern in terms of the synergistic paradigm. The patterns are compared with the morphological structures previously identified in clinical studies.


Role of ultrasonographic/clinical profile, cytology, and BRAF V600E mutation evaluation in thyroid nodule screening for malignancy: a prospective study.
Ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) is the most reliable nonsurgical test for distinguishing benign from malignant thyroid nodules. However, there is no consensus on which nodules should undergo FNAB. The aims of this study were to evaluate the utility of US-guided FNAB in the diagnostic assessment of nodules with or without clinical/US features suggestive for malignancy and to investigate the additional contribution of BRAF V600E mutation analysis in the detection of differentiated thyroid cancer. Thyroid cytoaspirates from 2421 nodules at least 4 mm in diameter were performed in 1856 patients who underwent cytological evaluation and biomolecular analysis. Cytology showed high positive predictive value and specificity for the diagnosis of malignant lesions. BRAF V600E mutation was found in 115 samples, 80 of which were also cytologically diagnosed as papillary thyroid cancer. BRAF mutation analysis significantly enhanced the diagnostic value of cytology, increasing FNAB diagnostic sensitivity for malignant nodules by approximately 28%. Micro PTC (63% of diagnosed papillary thyroid carcinoma) showed a high prevalence of multifocality, extrathyroidal extension, and lymph node metastases, underlining the malignant potential of thyroid microcarcinomas. Each investigated US/clinical characteristic of suspected malignancy correlated with the presence of a thyroid cancer in thyroid nodules with diameter of at least 4 mm. These data indicate that nodules of at least 4 mm may underlie a thyroid cancer independently of US/clinical characteristics of suspected malignancy, suggesting the need to perform FNAB. The diagnostic sensitivity for thyroid cancer is significantly increased by BRAF V600E mutation analysis, indicating that the screening for BRAF mutation in FNAB samples has a relevant diagnostic potential.


Primary structure of apolipophorin-III from the greater wax moth, Galleria mellonella.
The complete amino acid sequence of apolipophorin-III (apoLp-III), a lipid-binding hemolymph protein from the greater wax moth, Galleria mellonella, was determined by protein sequencing. The mature protein consists of 163 amino acid residues forming a protein of 18,075.5 Da. Its sequence is similar to apoLp-III from other Lepidopteran species, but remarkably different from the apoLp-IIIs of insects from other orders. As shown by mass spectrometric analysis, the protein carries no modifications. Thus, all of its known physiological functions, including its recently discovered immune response-stimulating activity, must reside in the protein itself.


Validated LC-MS/MS Method for the Simultaneous Determination of Amlodipine and Its Major Metabolites in Human Plasma of Hypertensive Patients.
No information on the pharmacokinetic characteristics of amlodipine (AML) metabolites is available. This study aimed to develop a method based on isocratic liquid chromatography coupled to tandem mass spectrometry for the simultaneous determination of AML and its 2 major metabolites, dehydroamlodipine (DH-AML) and O-des[2-aminoethyl]-O-carboxymethyl DH-AML (CM-DH-AML), and to use it for monitoring this drug in hypertensive patients. Acetonitrile-deproteinized plasma specimens were separated using an octadecyl-silica column (3-μm particle size) with a mobile phase consisting of 50% methanol containing 0.15% of formic acid in water. The run time was 9 minutes. The mass spectrometer was run in the positive ion electrospray ionization mode. This method was applied for the determination of AML and its metabolites in plasma samples from patients treated with this drug. The calibration curves in human plasma of AML, DH-AML, and CM-DH-AML were linear over the concentration ranges of 0.5-64, 1-64, and 0.5-64 ng/mL, respectively, and their lower limits of quantification were 0.5, 1, and 0.5 ng/mL, respectively. Their extraction recovery rates and matrix factors in human plasma were 94.8%-109.0% and 97.0%-101.4%, respectively. The intra-assay and interassay imprecisions and accuracies were within 10.8% and 95.4%-111.2%, respectively. The plasma concentration ranges of AML, DH-AML, and CM-DH-AML were 6.5-20.9, 1.4-10.9, and 5.6-38.3 ng/mL, respectively. The present method with acceptable analytical performance can be helpful for monitoring the plasma concentration of AML, including the determination of its metabolites in patients with hypertension.


Incorporating genomic, transcriptomic and clinical data: a prognostic and stem cell-like MYC and PRC imbalance in high-risk neuroblastoma.
Previous studies suggested that cancer cells possess traits reminiscent of the biological mechanisms ascribed to normal embryonic stem cells (ESCs) regulated by MYC and Polycomb repressive complex 2 (PRC2). Several poorly differentiated adult tumors showed preferentially high expression levels in targets of MYC, coincident with low expression levels in targets of PRC2. This paper will reveal this ESC-like cancer signature in high-risk neuroblastoma (HR-NB), the most common extracranial solid tumor in children. We systematically assembled genomic variants, gene expression changes, priori knowledge of gene functions, and clinical outcomes to identify prognostic multigene signatures. First, we assigned a new, individualized prognostic index using the relative expressions between the poor- and good-outcome signature genes. We then characterized HR-NB aggressiveness beyond these prognostic multigene signatures through the imbalanced effects of MYC and PRC2 signaling. We further analyzed Retinoic acid (RA)-induced HR-NB cells to model tumor cell differentiation. Finally, we performed in vitro validation on ZFHX3, a cell differentiation marker silenced by PRC2, and compared cell morphology changes before and after blocking PRC2 in HR-NB cells. A significant concurrence existed between exons with verified variants and genes showing MYCN-dependent expression in HR-NB. From these biomarker candidates, we identified two novel prognostic gene-set pairs with multi-scale oncogenic defects. Intriguingly, MYC targets over-represented an unfavorable component of the identified prognostic signatures while PRC2 targets over-represented a favorable component. The cell cycle arrest and neuronal differentiation marker ZFHX3 was identified as one of PRC2-silenced tumor suppressor candidates. Blocking PRC2 reduced tumor cell growth and increased the mRNA expression levels of ZFHX3 in an early treatment stage. This hypothesis-driven systems bioinformatics work offered novel insights into the PRC2-mediated tumor cell growth and differentiation in neuroblastoma, which may exert oncogenic effects together with MYC regulation. Our results propose a prognostic effect of imbalanced MYC and PRC2 moderations in pediatric HR-NB for the first time. This study demonstrates an incorporation of genomic landscapes and transcriptomic profiles into the hypothesis-driven precision prognosis and biomarker discovery. The application of this approach to neuroblastoma, as well as other cancer more broadly, could contribute to reduced relapse and mortality rates in the long term.


Mortality and renal prognosis in isolated metformin-associated lactic acidosis treated with continuous renal replacement therapy and citrate-calcium-anticoagulation.
Use of metformin increases plasma lactate concentration and may lead to metformin-associated lactic acidosis (MALA). Previous studies have suggested severe MALA to have a mortality of 17%-21%, but have included patients with other coincident conditions such as sepsis. The treatment of choice is continuous renal replacement therapy (CRRT), which has been performed using heparin analogues or no anticoagulation in former studies. Patients admitted to the Intensive Care Unit of Turku University Hospital Finland with lactic acidosis without any other recognizable etiology than concomitant metformin treatment who required CRRT between years 2010 and 2019 were included. CRRT was performed using regional citrate-calcium-anticoagulation. Data extracted included patient demographics, comorbidities, and clinical parameters at 6-hour intervals about 72 hours from admission. Creatinine and estimated glomerular filtration rate (eGFR) were measured at 1 year after MALA. A total of 23 patients with isolated MALA were included in the study. Median (IQR) pH was 6.88 (6.81-7.07) and lactate 16.1 (11.9-23.0) mmol/L on admission. Median (IQR) duration of CRRT was 62 (41-70) hours. Seven patients (30%) required mechanical ventilation with a mean duration of 6.0 ± 3.0 days. 90-day mortality was 4.3% and 1-year mortality 13.0%. Creatinine (P = .02) and eGFR (P = .03) remained significantly altered at 1 year of follow-up compared to baseline. MALA can be treated effectively and safely with CRRT and citrate-calcium-anticoagulation, usually required for 2-3 days. Mortality of patients with MALA treated with CRRT is low when other conditions inducing lactic acidosis are excluded. MALA episode may be associated with long-lasting kidney injury.


Valid or not? Yunnan mountain snake Plagiopholis unipostocularis (Serpentes: Colubridae: Pseudoxenodontinae).
Plagiopholis unipostocularis Zhao, Jiang & Huang, 1978 is a small snake endemic to Yunnan, southern China. Its validity is still controversial and unresolved. Based on extensive sampling in Yunnan, we conducted morphological comparison and molecular phylogenetics on the unidentified specimens of Plagiopholis from Yunnan. Based on a combination of morphological comparison and molecular phylogeny, the newly collected specimens could be identified as P. blakewayi. While some specimens exhibit one or more diagnostics of P. unipostocularis, and some characteristics are intermediate between that of Plagiopholis unipostocularis and P. blakewayi. Thus morphological continuities between two species uncovered P. unipostocularis is a synonymy of P. blakewayi, and the diagnostics of this species was revised accordingly.


The effect of incorporation, orientation and silane treatment of glass fibers on the fracture resistance of interim fixed partial dentures.
Fracture of interim fixed partial dentures (FPD) is of important concern to the dental surgeon, especially with long-span fixed partial dentures or areas of heavy occlusal stress. Polymers used in interim FPDs, reinforced with glass fibers have shown to have a positive effect on the fracture resistance of interim FPDs. Since little research has been done on the influence of silane treated glass fibers on the fracture resistance of interim FPDs, this study was conducted to evaluate the effect of silane treatment of glass fibers on the fracture resistance of interim FPDs and its correlation with the position of fiber reinforcement and length of the span of the interim FPD. Interim FPDs were fabricated from an autopolymerizing polymethyl methacrylate (PMMA) resin. Seven FPDs were made in each group. The FPDs in the control group were unreinforced, and in the other groups the FPDs were reinforced either with non silane treated glass fiber or with silane treated glass fiber. The fibers were placed in two different locations in the FPDs. Three length of span of FPDs were tested. The load was applied to the FPD by a steel ball placed in the center of the pontic space. One Way Anova, Two Way Anova, Studentized range test (Scheffe's). Results showed that the load required for fracturing the unreinforced FPDs varied from 272 to 998 N. Mean fracture load of reinforced FPDs varied from 536 to 1642 N. One-way analysis of variance showed that the position of fibers and the silane treatment fibers significantly affected the fracture load. The results of this study suggested that the silane treatment of glass fibers had a marked improvement in the fracture resistance of FPDs as compared to untreated glass fibers. Selective placement of the glass fibers at the undersurface of the pontic and the occlusal surface of the interim fixed partial denture showed more increase in the fracture resistance as compared to the randomly distributed glass fibers. The glass fiber reinforcement is effective in increasing the fracture resistance with the effectiveness most evident in interim FPDs with long spans. With increase in the length of span of interim fixed partial denture the fracture resistance was shown to decrease significantly in all the groups.


Increased hippocampal volume in schizophrenics' parents with ancestral history of schizophrenia.
Decreased hippocampal volume is one of the hypothesized pathological features of schizophrenia, but it is not known if this abnormality is familially transmitted. The aim of this study was to measure the hippocampal volume of the parents of schizophrenic probands, in relationship to the apparent transmission of genetic risk. Eighteen subjects from families consisting of a schizophrenic proband and two clinically unaffected parents were studied. Probands were compared to six control subjects, matched for age, sex, and educational level. The six families were selected so that only one parent had an ancestral family history of schizophrenia. The volumes of both hippocampi were measured by magnetic resonance imaging and adjusted for age and whole brain volume. The total hippocampal volumes of the parents with ancestral family history of schizophrenia were significantly larger than those of their schizophrenic offspring. This study suggests that decreased hippocampal volume in schizophrenia is not a familially transmitted abnormality. Rather, it appears that clinically unaffected parents who transmit apparent genetic risk for schizophrenia may have increased hippocampal volume, which may be a protective factor against the illness.


Asymmetric load-carrying in young and elderly women: relationship with lower limb coordination.
This study investigates balance during asymmetric load-carrying and how asymmetric loading affects lower limb coordination during gait. Walking with and without a hand-held bag was analyzed in five young and six elderly women using a 6-camera VICON system and two force plates. Balance and lower limb coordination were compared when walking with and without a bag and also between age groups. While carrying a bag, the trunk, head, and upper arm were recruited in both young and elderly women. With the load, the contralateral hip abduction torque increased, whereas the ipsilateral hip torque decreased. Intralimb and interlimb coordinations did not vary with the different load conditions. The only difference observed between the groups was the contralateral shoulder abduction. The elderly group abducted their shoulders to a greater extent, even when walking without a bag.


Production and characterization of monoclonal antibodies to peripheral and central nervous system myelin.
Monoclonal antibodies against P0, myelin basic protein, or myelin-associated glycoprotein were generated by fusing mouse myeloma cells with spleen cells from BALB/c mice immunized with central and peripheral nervous system myelin proteins. The antibodies secreted were either IgG, IgM, or IgA. Clone C6B5 (iso-type IgM) secreted antibody(ies) that bound to both myelin basic protein and myelin-associated glycoprotein, although binding of antibody to myelin basic protein as detected by the immunoblot technique appeared to be much less than to the myelin-associated glycoprotein. Antibodies were characterized in solid-phase radioimmunoassay for their species cross-reaction, and histologically for the specificity of binding to myelin in central and peripheral nervous system tissues. These monoclonal reagents should prove valuable in studying CSF and myelin-producing cells, since in both cases the concentration of myelin proteins is low.


Staying the distance: avoiding the proteasomal trap.
There are a multitude of nuclear receptor coactivators, and as a result, individual constituents of activation complexes are often overlooked when studying the specific actions of hormone signaling pathways. Specificity is typically associated with the receptor and its cognate ligand. However, SRC-3 has distinguished itself by persistent association with cell growth. In the February 29 issue of Molecular Cell, Yi et al. demonstrate that estrogen-induced posttranslational modulation of SRC-3 by atypical PKC shields it from proteasomal degradation, facilitating increased estrogenic gene activity. This process may have important implications in different types of hormone-sensitive tumors, particularly breast cancer.


Early postoperative acute abdominal complications.
The detection and management of acute postoperative conditions of the abdomen present a challenge to the surgeon. Many of these conditions threaten life because of their association with disorders of oxygenation, circulatory stability, and infection leading to multiple organ failure. This discussion highlights features of rapid diagnosis and focuses on problems relating to the decision to reoperate for diagnosis and therapy.


The risk of higenamine adverse analytical findings following oral administration of plumula nelumbinis capsules.
Higenamine is a β2-agonist that has been included in the Prohibited List of the World Anti-Doping Agency (WADA) since 2017. Meanwhile, it exists in plumula nelumbinis, a part of the lotus seed, and is commonly used as an ingredient in cuisines, herbal medicines, and nutritional supplements in China and other countries in East Asia. Therefore, an evaluation of the risk of an adverse analytical finding (AAF) of higenamine caused by plumula nelumbinis products is necessary in doping control. In this study, 14 volunteers took plumula nelumbinis capsules orally (0.34 g/caplet, 6 caplets/day, 7 days), and another 11 volunteers ingested higenamine tablets (three 5 mg tablets/day for 7 days). Urine samples were collected over a period of 14 days. All urine samples were subjected to quantitative dilute-and-shoot analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analytical results showed that urinary higenamine concentrations exceeded the WADA reporting limit (10 ng/mL) during the drug period in most sample groups. The maximum higenamine concentration observed in the plumula nelumbinis capsule group was 500 ng/mL. Based on confidence interval theory, appropriate data were used to establish mathematical models. The models reflected that the higenamine concentration in urine can exceed the WADA reporting limit with a high probability after taking plumula nelumbinis capsules. In conclusion, oral administration of plumula nelumbinis capsules showed a high risk of an AAF due to higenamine.


A methodological and functional proteomic approach of human follicular fluid en route for oocyte quality evaluation.
Human follicular fluid (HFF) has been proven to contain biologically active molecules and proteins that may affect follicle growth and oocyte fertilization. Based on this concept, HFF proteomic characterization is having a significant impact in the delineation of a biomarkers' profile for oocyte quality estimation and, maybe, for in vitro fertilization (IVF) success improvement. Follicular fluid is characterized by a vast protein complexity and a broad dynamic range of protein abundances that hinder its analysis. In this study we determined a proper solubilization and resolution method of HFF in 2-DE, minimizing sample manipulation, protein loss, and experimental artifacts. According to our methodology some low-abundance proteins were detected and identified by MS. Identified proteins were then functionally cross-linked by a pathway analysis. The generated path highlighted the occurrence in HFF of a tight functional-network in which effectors and inhibitors control and balance a space- and time-dependent induction/inhibition of inflammation, coagulation, and ECM degradation/remodeling. Such fine modulation of enzymatic activities exerts a fundamental role in follicle development and in oocyte competence acquiring. Alpha-1-antitrypsin resulted in the core protein of the delineated net and we interestingly detected its differential incidence in FF and serum from two small cohorts of patients who underwent IVF. Human ovarian follicular fluid (HFF) is the in vivo microenvironment for oocyte during folliculogenesis. It contains biologically active molecules that may affect oocyte quality, fertilization, and embryo development. HFF is also one of the most abundant "waste product" in assisted reproduction. This makes HFF a readily accessible source of biomolecules for competence evaluation of collected oocytes. The methodological improvement we obtained in proteomics characterization of HFF lead to a wide overview on the functional correlation existing between several fluid components and on how their aberrant occurrence/activity may affect oocyte quality and ovulation.


Targeting histone acetylation in pulmonary hypertension and right ventricular hypertrophy.
Epigenetic mechanisms, including DNA methylation and histone post-translational modifications (PTMs), have been known to regulate chromatin structure and lineage-specific gene expression during cardiovascular development and disease. However, alterations in the landscape of histone PTMs and their contribution to the pathogenesis of incurable cardiovascular diseases such as pulmonary hypertension (PH) and associated right heart failure (RHF) remain largely unexplored. This review focusses on the studies in PH and RHF that investigated the gene families that write (histone acetyltransferases), read (bromodomain-containing proteins) or erase (histone deacetylases [HDACs] and sirtuins [SIRT]) acetyl moieties from the ε-amino group of lysine residues of histones and non-histone proteins. Analysis of cells and tissues isolated from the in vivo preclinical models of PH and human pulmonary arterial hypertension not only confirmed significant alterations in the expression levels of multiple HDACs, SIRT1, SIRT3 and BRD4 proteins but also demonstrated their strong association to proliferative, inflammatory and fibrotic phenotypes linked to the pathological vascular remodelling process. Due to the reversible nature of post-translational protein acetylation, the therapeutic efficacy of numerous small-molecule inhibitors (vorinostat, valproic acid, sodium butyrate, mocetinostat, entinostat, tubastatin A, apabetalone, JQ1 and resveratrol) have been evaluated in different preclinical models of cardiovascular disease, which revealed the promising therapeutic benefits of targeting histone acetylation pathways in the attenuation of cardiac hypertrophy, fibrosis, left heart dysfunction, PH and RHF. This review also emphasizes the need for deeper molecular insights into the contribution of epigenetic changes to PH pathogenesis and therapeutic evaluation of isoform-specific modulation in ex vivo and in vivo models of PH and RHF. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.


Real-world accuracy of computed tomography in patients admitted with small bowel obstruction: a multicentre prospective cohort study.
Small bowel obstruction (SBO) is a common surgical emergency. Previous studies have shown the value computed tomography (CT) scanning in both confirming this diagnosis and identifying indications for urgent surgical intervention, such as strangulated bowel or closed loop obstructions. However, most of the literature is based on retrospective expert review of previous imaging and little data regarding the real-time accuracy of CT reporting is available. Here, we investigated the real-world accuracy of CT reporting in patients admitted with SBO. This was a multicentre prospective study including consecutive patients admitted with SBO. The primary outcomes were the sensitivity and specificity of CT scanning for bowel obstruction with ischaemia and closed loop obstruction. Data were retrieved from the original CT reports written by on-call radiologists and compared with operative findings. One hundred seventy-six patients were included, all of whom underwent CT scanning with intravenous contrast followed by operative management of SBO. Bowel obstruction with ischaemia was noted in 20 patients, with a sensitivity and specificity of CT scanning of 40.0% and 85.5%, respectively. Closed loop obstructions were noted in 26 patients, with a sensitivity and specificity of CT scanning of 23.1% and 98.0%, respectively. The real-world accuracy of CT scanning appears to be lower than previously reported in the literature. Strategies to address this could include the development of standardised reporting schemas and to increase the surgeon's own familiarity with relevant CT features in patients admitted with SBO.


Synthesis and evaluation of biological properties of benzylideneacetophenone derivatives.
A series of yakuchinone B 1f and its analogs 1a-e was synthesized and evaluated for free radical scavenging, suppression of LPS-induced NO generation, cytotoxicity and anti-excitotoxicity in vitro. Compound 1c exhibited potent anti-excitotoxicity, while all compounds 1a-f showed considerable effects of free radical scavenging, suppression of LPS-induced NO generation, and cytotoxicity in microglia.


[Availability of patient information in the emergency department : Wish and reality].
Fast access to information from other healthcare service providers is particularly important in emergency medicine, as the patients are often unknown and treatment decisions have to be made promptly. The study aims to identify the challenges that emergency departments face in obtaining information on patient history, the expected benefits of easier access to information and which information is most urgently needed. An online survey throughout Germany was carried out among medical staff working in emergency departments. In all, 181 questionnaires were fully completed and could be included in the data analysis. Of the respondents, 77.9% said it was difficult or very difficult to receive external data at the point of patient care. The survey participants estimate that they need an average of around 47 min to obtain information about one patient. 99.4% believe that patient care would benefit from an easier and faster information exchange. Medication lists, discharge letters, information on previous illnesses and allergies were classified as the most important data elements. There is an urgent need for action with regard to the considerable effort involved in obtaining information on emergency patients. Digital solutions such as the recently introduced emergency data set can offer additional value for clinical emergency care if they are widely used.


Legal, ethical and practical considerations in research involving nurses with dyslexia.
To discuss the legal, ethical and practical considerations in UK studies involving nurses with dyslexia and medication administration errors (MAEs). Nurses with dyslexia are a vulnerable population as they are susceptible to misrepresentation in research, especially that which involves a sensitive topic such as MAEs. Nurses with dyslexia may be particularly vulnerable to research that could exploit, implicate or attribute unsafe practice to them and their disability. Special consideration should be exercised when researching this population. Despite the potential for legal, ethical and practical issues, MAEs and nurses with dyslexia are under-researched areas and warrant further research. Benefits can be gained, not only by participants but also those with a vested interest in how best to support dyslexic nurses in clinical practice. Through effective design, risks can be identified and minimised, and the research made viable, ethically sound and ultimately beneficial to all those involved.


Benzodiazepine agonists reverse the effects of noise exposure on central benzodiazepine receptors and cardiac responsiveness.
Rats were submitted to 110 dB white noise exposure for 1, and 6 hours and brain alpha 1, beta 1 and benzodiazepine receptor binding was evaluated with selective ligands. An increase in cerebral benzodiazepine receptor (CBR) concentration, without any significant change in affinity constant, occurred after the 6 h treatment; no change was observed in adrenergic receptor binding at any period of exposure. Both diazepam and clonazepam pre-treatment reversed the effects of noise on CBR binding, confirming a role of these receptors in the response to noise stress. Furthermore, these benzodiazepine agonists influenced the response of cardiac and aortic tissues, which are known to be changed by stress exposure. Diazepam and clonazepam pre-treatment protected cardiac tissue from the effects of 6h noise stress, and a potentiation of aortic responses was detected, although at different times of exposure. The differences between the responses of these peripheral tissues to benzodiazepine treatment suggest that the expression depends on the tissue examined and the period of exposure.


Peroxisomal localization and activation by bivalent metal ions of ureidoglycolate lyase, the enzyme involved in urate degradation in Candida tropicalis.
Ureiodoglycolate lyase (EC 22.214.171.124) was found only in the peroxisomes in urate-induced Candida tropicalis. The enzyme was markedly activated by the bivalent metal ions Mn2+, Fe2+, and Ni2+. The activation by Mn2+ was suggested to be the result of its binding to the apoenzyme.


Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation.
We conducted a phase II study to assess the efficacy of continuous dosing of sunitinib in patients with flurodeoxyglucose positron emission tomography (FDG-PET)-avid, iodine-refractory well-differentiated thyroid carcinoma (WDTC) and medullary thyroid cancer (MTC) and to assess for early response per FDG-PET. Patients had metastatic, iodine-refractory WDTC or MTC with FDG-PET-avid disease. Sunitinib was administered at 37.5 mg daily on a continuous basis. The primary end point was response rate per Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included toxicity, overall survival, and time to progression. We conducted an exploratory analysis of FDG-PET response after 7 days of treatment. Thirty-five patients were enrolled (7 MTC, 28 WDTC), and 33 patients were evaluable for disease response. The primary end point, objective response rate per RECIST, was 11 patients (31%; 95% confidence interval, 16-47%). There were 1 complete response (3%), 10 partial responses (28%), and 16 patients (46%) with stable disease. Progressive disease was seen in 6 patients (17%). The median time to progression was 12.8 months (95% confidence interval, 8.9 months-not reached). Repeat FDG-PET was done on 22 patients. The median percent change in average standardized uptake values was -11.7%, -13.9%, and 8.6% for patients with RECIST response, stable disease, and progressive disease, respectively. Differences between response categories were statistically significant (P = 0.03). The most common toxicities seen included fatigue (11%), neutropenia (34%), hand/foot syndrome (17%), diarrhea (17%), and leukopenia (31%). One patient on anticoagulation died of gastrointestinal bleeding. Continuous administration of sunitinib was effective in patients with iodine-refractory WDTC and MTC. Further study is warranted.


Development and validation of a liquid chromatography-mass spectrometry method for simultaneous analysis of triazine-based brominated flame retardants in environmental samples.
In the present study, a novel and reliable analytical method was developed and validated for the simultaneous determination of 1,3,5-tris(2,3-dibromopropyl)-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (TDBP-TAZTO) and 2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine (TTBP-TAZ) in environmental samples using high-performance liquid chromatography coupled to a tandem mass spectrometer. Firstly, for optimization of the liquid chromatography separation, mobile phases, oven temperatures, modifiers, and buffers were varied. Afterwards, the extraction efficiency of sediment and fish samples was tested with different techniques (pressurized liquid, solid-liquid, ultrasound-assisted, and Soxhlet extraction). Additionally, cleanup using modified multilayer silica gel (sediment) and gel permeation chromatography as well as Florisil® columns (fish) with several solvent mixtures were performed. The best results were obtained with the pressurized liquid extraction (optimal conditions: extraction solvent 100% toluene, extraction time 20 min, cycles two, extraction temperature 100 °C, and flushing volume 60%) compared to other solvent extraction methods. On the basis of this optimized analytical procedure, the method was validated with satisfactory values of correlation coefficient (R2) between 0.998 and 0.999 for both matrices in the calibration range of 2.0-502.0 μg kg-1 for TDBP-TAZTO and 16.6-770.6 μg kg-1 for TTBP-TAZ in sediment samples as well as 4.8-303.5 μg kg-1 and 47.4-742.5 μg kg-1 in fish samples (bream), respectively. Mean recoveries (n = 5) were calculated for both analytes with spiked matrices at one concentration level (100 μg kg-1) between 98 and 114% with intra-day relative standard deviations less than 11%. The inter-day precision (n = 15) was also acceptable for both compounds < 11%. It was found that the limit of detection and limit of quantification were in the range of 0.4-1.3 μg kg-1 for TDBP-TAZTO and 10-28 μg kg-1 for TTBP-TAZ in surface sediment samples and 7-25 μg kg-1 and 22-80 μg kg-1 in fish samples (bream), respectively. The results indicated that these analytical methods could provide reliable and efficient approaches for quantification of TDBP-TAZTO and TTBP-TAZ in sediment and fish samples. Graphical abstract.


Progressive reactive lymphoid connective tissue disease and development of autoantibodies in scavenger receptor A5-deficient mice.
Scavenger receptor A5 (SCARA5) is a member of the class A scavenger receptors, with most similarity to SCARA1 (SR-A) and SCARA2 (MARCO), which are primarily expressed by macrophages and dendritic cells, in which they participate in clearance of various polyanionic macromolecules, pollution particles, and pathogens. The biological role of SCARA5 has been unknown. Herein, we show that SCARA5 is an endocytotic receptor whose ligand repertoire includes the typical scavenger receptor ligands, whole bacteria, and purified Gram-negative bacterial lipopolysaccharide. In contrast to expression of SCARA1 and SCARA2 in immune cells, SCARA5 is found in a subset of fibroblast-like cells in the interstitial stroma of most organs, with additional expression in the epithelial cells of testis and choroid plexus. SCARA5-null mice develop with age lymphoid cell accumulation in many organs, in particular the lungs, and show decreased endocytotic function in fibroblasts. Furthermore, about one-third of the mice develop antinuclear antibodies. These disturbances are reminiscent of those found in many human autoimmune connective tissue disorders, which suggests that defects in fibroblast SCARA5 can underlie some forms of autoimmune disease.


Technical concept of patient-specific, ultrahigh molecular weight polyethylene orbital wall implant.
The authors have been using patient-specific implants since 2006 and are constantly looking for new reconstructive materials, in order to create precise implants for orbital reconstruction. Such materials should be biocompatible and stable in the human body, as well as easy to machine and form into complex 3D shapes. Biocompatible ultrahigh molecular weight polyethylene (UHMW-PE) has several unique properties including high impact strength and a low friction coefficient that result in self-lubricating and thus non-sticking surfaces after processing. To present the concept of a patient-specific, UHMW-PE orbital wall implant. The material used to manufacture the orbital implant was UHMW-PE converted into a solid block of medical polymer from a powder material. A delayed treatment unilateral orbital fracture case was chosen for reconstruction with patient-specific orbital wall implant. On the basis of computerized tomography, a virtual model of both orbits was prepared. The injured orbit was significantly enlarged due to dislocation of its walls. The 3D model of the facial skeleton was symmetrically divided into two parts. This resulted in two models - left and right orbit, then the uninjured orbit was superimposed onto the contralateral side. As a result two surfaces were created; the outer surface (taken from the injured orbit) was used to design the outer surface of the implant, and the inner (taken from the uninjured orbit) for the inner surface. By combining both these surfaces it was possible to determine the unique shape and thickness of the UHMW-PE implant that would allow for accurate reconstruction of the orbit. Following this, the CAD model was transferred to CAM software and a numerical code for a 5-axis milling machine was generated. The manufactured implant was sterilized in gas plasma and used to reconstruct three orbital walls. The thickness of the manufactured implant ranged from 0.2 mm to 1.5 mm and was successfully inserted via transconjunctival approach. The lower, medial and lateral walls were reconstructed. The correct position of the right eyeball was re-established by moving it upward and medially, which resulted in enophthalmos and diplopia correction. The described method features several advantages: accurate reconstruction of the original shape of the orbit, precise modification of local implant thickness during design of the CAD model, structural globe support combined with a thin implant, the possibility of repairing large orbital floor defects, corrections using scissor/scalpel during surgery are relatively uncomplicated, low level of morbidity, smooth edges and gradual, controlled variations in implant thickness between different regions. Disadvantages: changes to the curvature of the implant cannot be made during surgery, implant may require fixing with screws to be stabilized during the early phase of healing, long time required to design and manufacture implants (pre-op) and also UHMW-PE implants are radiolucent and cannot be imaged using X-rays. UHMW-PE appears to have numerous advantages as a material for precise reconstruction of the orbits. Such patient-specific implants are durable, can even be used to reconstruct very thin walls, do not exhibit the high degree of morbidity typical for autogenous bone grafts and result in restoration of vision function.


Down-regulation of retroviral transgene expression during differentiation of progenitor-derived dendritic cells.
Hematopoietic progenitor cells are a promising source for generation of genetically modified dendritic cells. A prerequisite for using these cells in therapeutic approaches is stable vector-mediated transgene expression during and after cell maturation. We investigated the expression of enhanced green fluorescence protein (EGFP) mediated by retroviral vectors in dendritic cells and other hematopoietic cells differentiated in vitro. CD34(+) cells were efficiently transduced with retroviral vector constructs known to mediate different expression levels due to distinct cis-acting elements. EGFP(+) cells were purified by cell sorting and differentiated to monocytes, granulocytes, dendritic cells, and erythrocytes. Coexpression of EGFP and cell type-specific markers was analyzed by flow cytometry. Transgene expression from various retroviral vectors was silenced exclusively in dendritic cells, but not in other mature myeloid cells. Loss of EGFP was most pronounced in cells initially displaying low expression levels. This was confirmed by using a retroviral vector coding for a variant of EGFP with significantly reduced half-life. In contrast, a majority of dendritic cells showed stable expression when a self-inactivating retroviral construct using an internal cytomegalovirus promotor was used. We suggest that expression from the retroviral long terminal repeat is silenced during dendritic cell differentiation in vitro. High levels of stable transgene product in progenitor cells may mask a loss of expression. An improvement of retroviral vectors mediating stable transgenic expression is necessary for therapeutic approaches using gene-modified dendritic cells.


Viper venom induced inflammation with Montivipera xanthina (Gray, 1849) and the anti-snake venom activities of Artemisia absinthium L. in rat.
The present study was conducted to explore the characterization of Montivipera xanthina crude venom partially by in vitro and in vivo and the anti-snake venom activities of Artemisia absinthium L. in comparison with carrageenan-induced acute inflammation model in rats. The LD50 value was estimated as 8.78 mg/kg within 24 h by different venom doses administrated intraperitoneally in mice. The IC50 value was 0.43 ± 0.18 μg/ml after 48 h treatment while the calculated value was 0.73 ± 0.10 μg/ml for the culture media totally refreshed after 2 h treatment with venom. Wistar rats were treated intraperitoneally with A. absinthium extract, 30 min before venom or carrageenan was injected subplantarly into the left hind paw. Intraperitoneal administration of 25 and 50 mg/kg extract was inhibited venom induced paw swelling at 0.5, 1, 2 and 3 h (p < 0.05) while 12.5, 25 and 50 mg/kg extract treatment was inhibited carrageenan-induced paw swelling at 2, 3, 4 and 5 h (p < 0.05). In conclusion, the in vivo toxicity and inflammatory actions and in vitro cytotoxic actions of crude M. xanthina venom were performed as a first report and inhibition of venom-induced inflammation by methanolic extract of A. absinthium was described.


Correlations between moral courage, moral sensitivity, and ethical decision-making by nurse interns: a cross-sectional study.
Clinical decision-making involves ethical issues that become more and more complex. Nurse interns must be more skilled in making rational and timely decisions when facing ethical dilemmas. The contributing factors and their relationships that challenge ethical decision-making among nurse interns must be fully understood, as this level of knowledge can support the development of strategies and interventions that improve the ethical decision-making ability of nurse interns. This study examined the relationships between moral courage, moral sensitivity, and ethical decision-making by nurse interns. In addition, we investigated whether moral sensitivity mediates the relationship between moral courage and ethical decision-making. A descriptive cross-sectional study using an online questionnaire. The study sampled nurse interns from Class iii Grade A general hospitals in Sichuan Province, China. A convenience sampling method was used to select 1334 nurse interns from March 2022 to May 2022. A general information questionnaire, the Nurses' Moral Courage Scale (NMCS), the Chinese Moral Sensitivity Questionnaire (MSQ), and the Judgement About Nursing Decision (JAND) were used for data collection. Data was processed and analysed using SPSS 26.0 and Amos 28.0. Data analysis included descriptive statistics, Pearson correlation analysis, and structural equation modelling. Moral courage was found to be positively correlated with ethical decision-making (P < 0.01). Moral sensitivity was also positively correlated with ethical decision-making (P < 0.01) and had a mediating effect on the relationship between moral courage and ethical decision-making (P < 0.01). The moral courage and moral sensitivity of nurse interns are positively correlated with ethical decision-making ability. Moral sensitivity significantly mediates the relationship between moral courage and ethical decision-making ability. The knowledge gained from this study can inform educational strategies and interventions in supporting the development of nurse interns' ethical decision-making ability.


RNA splicing regulates agrin-mediated acetylcholine receptor clustering activity on cultured myotubes.
Agrin is a component of the synaptic basal lamina that induces the clustering of acetylcholine receptors (AChRs) on muscle fibers. A region near the carboxyl terminus of the protein exists in four forms that are generated by alternative RNA splicing. All four alternatively spliced forms of agrin are active in inducing AChR clusters on rat primary and C2-derived muscle fibers. In contrast, only two forms of the protein, each containing an 8 amino acid insert, are capable of inducing clusters on myotubes of S27 cells, a C2 variant that has defective proteoglycans. These two forms are also most active in inducing clusters on chick myotubes. This pattern of differential activity suggests that RNA splicing of agrin transcripts and interactions with proteoglycans or other components of basal lamina have important roles in regulating the localization of neurotransmitter receptors at synaptic sites.


Native sulfur/chlorine SAD phasing for serial femtosecond crystallography.
Serial femtosecond crystallography (SFX) allows structures to be determined with minimal radiation damage. However, phasing native crystals in SFX is not very common. Here, the structure determination of native lysozyme from single-wavelength anomalous diffraction (SAD) by utilizing the anomalous signal of sulfur and chlorine at a wavelength of 1.77 Å is successfully demonstrated. This sulfur SAD method can be applied to a wide range of proteins, which will improve the determination of native crystal structures.


Visual resolution and sensitivity in a nocturnal primate (galago) measured with visual evoked potentials.
Visual resolution and contrast sensitivity were examined in anesthetized, paralyzed galagos using visual evoked potentials (VEPs) resulting from stimulation with phase-reversed sinewave gratings. Spatial frequency vs contrast response functions were band-pass with peak sensitivity at 0.2-0.4 c/deg and a high frequency cut-off between 1.6 and 3 c/deg. Peak contrast sensitivities (estimated from extrapolation of contrast response functions) varied across animals from 10 to 170. Variation of the stimulus modulation rate showed that best responses occurred at 1 Hz with an upper limit of 6-16 Hz. As in other primates, an oblique effect was seen in 6 of 8 animals. The contrast sensitivity function (CSF) determined from cortical VEPs agrees well with the CSFs of cells in the lateral geniculate nucleus, but peak sensitivity and spatial frequency are slightly lower than found for the behavioral CSF. Overall visual performance resembled closely that of another nocturnal species, the cat.


Procedure to prevent cast breakage during separation from elastomeric impressions.
This article describes a quick and simple procedure for removing dental stone casts from elastomeric impressions. Frequently, dental stone casts break at the time of separation because of the rigidity of the impression material. The materials used in this technique are inexpensive and easy to use. When this method is properly used, it simplifies the removal of the cast from the impression, decreasing the chance of fracture of the cast.


Determining the association of high-commitment human resource practices with nurses' compassionate care behaviour: A cross-sectional investigation.
The aim of this study was to determine the association of high-commitment human resource practices (HCHRPs) with nurses' compassionate care behaviour. The extant research highlights the key role of compassionate care behaviour in achieving quality health services. However, scant attention has been paid to identifying the factors that augment compassionate care behaviour among health care professionals. This study took place from September 2018 to March 2019, collecting data from 340 nurses of either gender aged 24-60 years with at least 1 year experience. The study follows a cross-sectional research design by collecting data through a personally administered survey. A statistically significant association was found between the four dimensions of HCHRPs and organisational commitment. Moreover, organisational commitment positively related to compassionate care behaviour and mediated the relationship between HCHRPs and compassionate care behaviour. The findings reveal that four dimensions of HCHRPs positively influence nurses' compassionate care behaviour via the indirect path of organisational commitment. The study marks the first attempt to delineate the role of HCHRPs in enhancing the compassionate care behaviour. The hospital administration and human resource managers should use HCHRPs as strategic imperative to attract competent employees and enhance compassionate care behaviour.


Four cases of chylous fistula after breast cancer resection.
Chylous fistulas in cases treated surgically for breast cancer only, are rare. We encountered four chylous fistula cases after breast cancer operations out of a total of 851 cases, all of which involved the left breast. Chylous fistulas were confirmed by axillary white fluid and were unrelated to obesity, surgical method or the area of axillary lymph node dissection. All four cases of chylous fistulas were successfully treated conservatively, with no special dietary control and no surgical treatment.


Response to Comment on "Unexpected reversal of C3 versus C4 grass response to elevated CO2 during a 20-year field experiment".
Nie and colleagues suggest a key role for interannual climate variation as an explanation for the temporal dynamics of an unexpected 20-year reversal of biomass responses of C3-C4 grasses to elevated CO2 However, we had already identified some climate-dependent differences in C3 and C4 responses to eCO2 and shown that these could not fully explain the temporal dynamics we observed.


Correction: Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition.
[This corrects the article DOI: 10.18632/oncotarget.16657.].


Direct photoreactive immobilization of water-soluble phospholipid polymers on substrates in an aqueous environment.
The purpose of this study is to achieve a simpler and safer surface modification of substrates using a photoreactive polymer in an aqueous environment. We synthesized water-soluble photoreactive polymers with both phenylazide groups and phosphorylcholine groups, poly(2-methacryloyloxyethyl phosphorylcholine-co-4-methacryl tetra(ethylene glycol)oxycarbonyl-4-phenylazide) (PMEPAz), via reversible addition fragmentation chain transfer polymerization. PMEPAz with different polymerization degrees were synthesized with a well-defined structure. To immobilize PMEPAz on the substrate surface by photoreaction, it is necessary to adsorb the polymer on the substrate surface in an aqueous solution because the phenylazide groups chemically bind to the substrate via a hydrogen abstract reaction. The relationship between the polymer solubilization state in the aqueous solution and the adsorption behavior at the surface was investigated. PMEPAz began to form unstable molecular aggregates at a concentration of 10-2 mg/mL and formed stable aggregates at 100 mg/mL. At a concentration of 10-1 mg/mL, unstable molecular aggregates of PMEPAz were formed in the aqueous solution, resulting in the maximization of the amount of adsorbed polymer and effective photoreaction with the substrate. The thickness of the reacted polymer layer on the substrate increased with an increase in the polymerization degree, a uniform polymer layer with a thickness of 3.4 nm was formed when the polymerization degree was 400. After surface modification, the hydrophobic surfaces of the original substrates became hydrophilic. Additionally, fibrinogen adsorption and platelet adhesion were effectively suppressed based on the characteristics of the phosphorylcholine unit.


Antibacterial activity of ruthenium polypyridyl complexes against Staphylococcus aureus and biofilms.
There is clearly a need for the development of new classes of antimicrobials to fight against multidrug-resistant bacteria. Here, we designed and synthesized of three ruthenium polypyridyl complexes: [Ru(bpy)2(BTPIP)](ClO4)2 (Ru(II)-1), [Ru(bpy)2(ETPIP)](ClO4)2 (Ru(II)-2) and [Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-3) (N-N = bpy = 2,2'-bipyridine), their antimicrobial activities against S. aureus were assessed. The lead complexes of this set, Ru(II)-1(MIC = 0.016 mg/mL), was tested against biofilm. We also investigated whether bacteria can easily develop resistance to Ru(II)-1. The result demonstrated that S. aureus could not easily develop resistance to the ruthenium complexes. In addition, aimed to test whether ruthenium complexes treatment could increase the susceptibility of S. aureus to antibiotics, the synergism between Ru(II)-1 and common antibiotics against S. aureus were investigated using the checkerboard method. Interesting, Ru(II)-1 could increased the susceptibility of S. aureus to some aminoglycoside antibiotics(kanamycin and gentamicin). Finally, in vivo bacterial infection treatment studies were also conducted through murine skin infection model. These results confirmed ruthenium complexes have good antimicrobial activity in vitro and in vivo.


Isolation, characterisation and genome analysis of a novel ginsenosides hydrolysing bacterium Ginsengibacter hankyongi gen. nov., sp. nov. isolated from soil.
A novel yellow-pigmented bacterial strain (designated BR5-29T), was isolated and its taxonomy was studied. Phylogenetic study based on the 16S rRNA and draft genome sequence placed the strain BR5-29T in a distinct lineage within the family Chitinophagaceae, sharing ≤ 93.4% sequence similarity with members of the closely related genera Ferruginibacter, Flavisolibacter, Flavitalea and Niastella. The novel isolate showed the highest sequence similarity to the genus Ferruginibacter. The draft genome of strain BR5-29T had a total length of 5,505,520 base pairs. A total of 4585 genes were identified, in which 4537 were CDS and 48 RNA genes were assigned a putative function. The genome annotation of BR5-29T showed 225 carbohydrate genes which may be responsible for the conversion of major ginsenosides to minor ginsenosides. Strain BR5-29T contained MK-7 as a predominant quinone, and iso-C15:0, iso-C15:0 G, iso-C17:0 3-OH, and C16:1 ω7c and/or C16:1 ω6c (summed feature 3) as major fatty acids. The polar lipids found in the strain BR5-29T were phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), five unidentified polar lipids (L1-L5), two unidentified aminolipid and one unidentified aminophospholipid. Our pilot data demonstrate that the novel isolate shares the similar major polar lipid PE, major quinone MK-7 and major fatty acids with the described members of the family Chitinophagaceae. However, the low 16S rRNA gene sequence (< 93.4%), the little high amount of C12:0, iso-C17:0 2-OH and iso-C15:1 2-OH fatty acids, low DNA G + C content, and the presence of DPG, PG and two unidentified polar lipids (L1 and L3 differentiate the BR5-29T from its closest phylogenetic neighbors. Thus, the isolate represents a novel genus and species in the family Chitinophagaceae for which the name Ginsengibacter hankyongi gen. nov., sp. nov. is proposed. The type strain is BR5-29T (= KACC 19446T = LMG 30462T). Thus, we predict that this novel strain may prove useful for the future research analysis (target gene cloning) and mass production of Rg3.


Submucosal gland cells in human lower airways produce MUC5AC protein.
It is now considered that the major component of mucus, MUC5AC, is mainly produced by goblet cells but not submucosal glands, and the role of the submucosal glands in the production of MUC5AC is unclear. The aim of this study was to clarify whether human submucosal glands produce MUC5AC. Immunohistochemical analysis with MUC5AC antibody of lower airways resected from six lung cancer patients and three patients with acute myocardial infarction was performed. The submucosal glands contained both MUC5AC-positive cells and non-positive cells. These data suggest that MUC5AC protein is produced in both goblet cells and in airway submucosal glands.


Prostate cancer cells metabolize d-lactate inside mitochondria via a D-lactate dehydrogenase which is more active and highly expressed than in normal cells.
Although D-lactate metabolism has been shown to occur in a variety of mitochondria, the metabolic fate of D-lactate in cancer cells has never been investigated, as it is believed to be exported to the extracellular phase. We show that mitochondria from both cancer (PC-3) and normal (PNT1A) prostate cells can metabolize D-lactate in an energy competent manner. This is due to the mitochondrial D-lactate dehydrogenase, a membrane flavoprotein, the activity and protein level of which are higher in PC-3 than in PNT1A cells, as detected by both kinetic and immunological analysis. D-Lactate can enter prostate mitochondria and cause the export of newly synthesized malate in a carrier-mediated manner, with the rate of malate efflux from mitochondria twofold higher in cancer.


Human Cytomegalovirus (HCMV) - specific T-cell response after letermovir prophylaxis is predictive for subsequent HCMV reactivation in haematopoietic stem cell transplant recipients.
Human Cytomegalovirus (HCMV) is still one of the major concerning infection in hematopoietic stem cell transplant (HSCT) recipients. Letermovir (LTV) has been recently introduced for HCMV prophylaxis in adult patients who received allogeneic HSCT. However, many aspects related to immune reconstitution need to be further explored. The aim of this study was to define the prognostic role of HCMV-specific T-cell frequency measured at the end of LTV prophylaxis in predicting the risk for clinically significant HCMV infection (i.e. infection requiring antiviral treatment) after the stop of the prophylaxis. Sixty-six adult patients who underwent allogeneic HSCT were enrolled and HCMV DNAemia was prospectively monitored. Additionally, HCMV-specific T-cell response was evaluated using ELISpot assay against two different antigens (HCMV infected cell lysate and pp65 peptide pool). Ten patients (15.2%) developed at least one positive HCMV DNAemia episode during LTV prophylaxis, whereas 50/66 (75.8%) patients developed at least one positive HCMV DNA event after LTV prophylaxis. Of note, 25 of them (50%) experienced a clinically significant HCMV infection. The median HCMV-specific T-cell response measured against HCMV lysate but not against pp65 peptide pool was lower in patients who developed HCMV clinically significant infection after prophylaxis. A ROC analysis revealed that the level of 0.04 HCMV-specific T cells/µl should be used as cut-off for development of clinically significant HCMV reactivation after prophylaxis. Assessment of HCMV-specific immunity upon discontinuation of universal prophylaxis with LTV should be considered as a method for identification of patients at risk for clinically significant HCMV infection.


The association between hemispheric specialization for language production and for spatial attention depends on left-hand preference strength.
Cerebral lateralization for language production and spatial attention and their relationships with manual preference strength (MPS) were assessed in a sample of 293 healthy volunteers, including 151 left-handers, using fMRI during covert sentence production (PROD) and line bisection judgment (LBJ) tasks, as compared to high- and low-level reference tasks. At the group level, we found the expected complementary hemispheric specialization (HS) with leftward asymmetries for PROD within frontal and temporal regions and rightward asymmetries for LBJ within frontal and posterior occipito-parieto-temporal regions. Individual hemispheric (HLI) and regional (frontal and occipital) lateralization indices (LI) were then calculated on the activation maps for PROD and LBJ. We found a correlation between the degree of rightward cerebral asymmetry and the leftward behavioral attentional bias recorded during LBJ task. This correlation was found when LBJ-LI was computed over the hemispheres, in the frontal lobes, but not in the occipital lobes. We then investigated whether language production and spatial attention cerebral lateralization relate to each other, and whether manual preference was a variable that impacted the complementary HS of these functions. No correlation was found between spatial and language LIs in the majority of our sample of participants, including right-handers with a strong right-hand preference (sRH, n=97) and mixed-handers (MH, n=97), indicating that these functions lateralized independently. By contrast, in the group of left-handers with a strong left-hand preference (sLH, n= 99), a negative correlation was found between language and spatial lateralization. This negative correlation was found when LBJ-LI and PROD-LI were computed over the hemispheres, in the frontal lobes and between the occipital lobes for LBJ and the frontal lobes for PROD. These findings underline the importance to include sLH in the study sample to reveal the underlying mechanisms of complementary HS.


Responses of Trollius chinensis to drought stress and rehydration: From photosynthetic physiology to gene expression.
Drought stress occurs more frequently in recent years due to the global climate change. Widely distributed in northern China, Mongolia, and Russia, Trollius chinensis Bunge has high medicinal and ornamental values and is often exposed to drought stress, while the mechanism underlying its drought response is still unclear. In this study, we applied 74-76% (control, CK), 49-51% (mild drought), 34-36% (moderate drought), and 19-21% (severe drought, SD) of the soil gravimetric water content to T. chinensis, and measured leaf physiological characteristics on the 0, 5th, 10th, 15th day after the soil reaching the set drought severities, and on the 10th day after rehydration. The results showed that many physiological parameters, such as chlorophyll contents, Fv/Fm, ΦPSⅡ, Pn, and gs decreased with the deepening of severity and duration of drought stress and recovered to some extent after rehydration. On the 10th day of drought stress, leaves in SD and CK were selected for RNA-Seq, and 1649 differentially expressed genes (DEGs) were found, including 548 up-regulated and 1101 down-regulated DEGs. Gene Ontology enrichment found that the DEGs were mainly enriched in catalytic activity and thylakoid. Koyto Encyclopedia of Genes and Genomes enrichment found that DEGs were enriched in some metabolic pathways such as carbon fixation and photosynthesis. Among them, the differential expression of genes related to photosynthesis process, ABA biosynthesis and signaling pathway, such as NCED, SnRK2, PsaD, PsbQ, and PetE, might explain why T. chinensis could tolerate and recover from as long as 15 days of severe drought conditions.


Molecular characterization of Clostridium tetani strains by pulsed-field gel electrophoresis and colony PCR.
Pulsed-field gel electrophoresis and PCR were applied for the first time to the molecular characterization of Clostridium tetani. Among five strains tested, one (CN1339) turned out to contain a mixture of two genetically different clones and two (D11 and G761) to contain bacteria differing by the presence or absence of the 74-kb plasmid harboring the tetX gene.


Size effect of single-walled carbon nanotube on adsorption of perfluorooctanesulfonate.
Perfluorooctanesulfonate (PFOS) is a typical persistent organic pollutant of more environmental concerns in the recent years. The adsorption of PFOS on the single-walled carbon nanotube (SWCNT) is studied with molecular dynamics (MD) simulation. The energy and conformational features are investigated via the statistical results from the MD trajectory. The size effect is observed from the adsorption of PFOS both on the inner and the outer surface. The non-bond interaction energy between PFOS and the inner surface of SWCNT is highly related to the diameter of nanotube. The conformation of PFOS is also changed by the sorbent surface. The PFOS molecule adsorbed on the outer surface is affected by the size of SWCNT more gently than that adsorbed in the nanotube. The aliphatic chain contributes most to the adsorption, as it locates more closely to the outer surface than the charged sulfuric group.


Land Plant Model Systems Branch Out.
The genome of the liverwort Marchantia polymorpha is an important step toward development of a new plant model system (Bowman et al., 2017). Liverworts may be the sister taxon to all other land plants, and the genome shows features that illuminate the ancestor of all land plants and give insights into how plant systems function and evolved.


Synergistic performance evaluation of MoS2-hBN hybrid nanoparticles as a tribological additive in diesel-based engine oil.
In this study, MoS2-hBN hybrid nanoparticles were synthesized using an advanced microwave platform for new nanolubricant formulations. The synthesized nanoparticles were characterized by field-emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, and Raman spectroscopy. The hybrid nanoparticles were then introduced into a 20W40 diesel-based engine oil to produce a nanolubricant. The physical and chemical properties of the nanolubricant were investigated, including the viscosity index, stability, volatility, tribological properties, oxidation properties, and thermal conductivity. The results showed that the inclusion of 0.05 wt% MoS2-hBN hybrid nanoparticles in the oil significantly reduced the coefficient of friction and wear scar diameter by 68.48% and 35.54%, respectively. Moreover, it exhibited substantial oxidation and thermal conductivity improvement of 38.76% and 28.30%, respectively, at 100 °C. These findings demonstrate the potential of MoS2-hBN hybrid nanoparticles as an effective additive to enhance the properties of nanolubricant significantly. Furthermore, this study offers valuable insights into the underlying mechanisms responsible for the observed enhancements. The promising outcomes of this investigation contribute to the advancement of nanotechnology-based lubricants, showcasing their potential for improving engine efficiency and prolonging the lifespan of machinery.


Reappraisal of optimal hemoglobin standards for female blood donors in Canada.
A hemoglobin (Hb) standard of 115 g per L on the copper sulfate test has been in use by the Canadian Red Cross Society Blood Services for female blood donor predonation screening since 1989. To determine if this lowered Hb standard results in increased iron deficiency in repeat blood donors, a study was conducted to evaluate the performance of the copper sulfate test and predonation capillary and venous Hb assays in a population of female blood donors most at risk of developing iron deficiency. Of the 174 donors who were of childbearing age, who were not taking iron supplements, and who had made at least three blood donations per year, 45 (25.9%) were iron deficient, and 64 (36.8%) had reduced iron stores; only 65 (37.3%) had normal iron stores. This study showed that capillary blood is more likely to have a higher Hb concentration (3.2 +/- 7.8 g/L) than venous blood samples, which could affect the performance of predonation screening assays that are based on capillary blood samples at a given discriminating value. With an Hb standard of 115 g per L, both the copper sulfate and capillary Hb assays were not sensitive enough to screen for iron deficiency (sensitivity, 27% and 33%; specificity, 96% and 93%, respectively) and were comparable only to the performance of a venous Hb assay with a cutoff value of 110 g per L (sensitivity, 27%; specificity, 99%). In contrast, an Hb standard of 125 g per L in the copper sulfate test could achieve a more optimal sensitivity of 79 percent and specificity of 78 percent. This study supports the use of a higher Hb cutoff value of 125 g per L for female blood donors in the predonation fingerstick copper sulfate test.


Chemokine receptor expression and chemotactic responsiveness of human monocytes after influenza A virus infection.
Chemokines and their receptors play an important role in site-directed migration and activation of leukocytes. To understand how viral infections may impair this function, we analyzed chemokine receptor expression and responsiveness of human monocytes after infection with influenza A virus. Whereas treatment with infectious virus induced a rapid down-regulation of the CCL2/monocyte chemoattractant protein-1 (MCP-1)-specific receptor CCR2, inactivated virus did not significantly alter CCR2 surface expression. In parallel, the response to CCL2/MCP-1 was lost after infection with active virus: Neither a CCL2/MCP-1-induced shift of intracellular calcium concentrations nor the chemotactic response to CCL2/MCP-1 was detectable. In striking contrast, the presence of CCR1 and CCR5 on the cell surface remained unchanged or was even slightly up-regulated after viral infection. However, the remaining expression of CCR1 and CCR5 correlated reciprocally with an ongoing unresponsiveness to the CCR1 and CCR5 agonists CCL3/macrophage-inflammatory protein-1alpha (MIP-1alpha), CCL4/MIP-1beta, and CCL5/regulated on activation, normal T expressed and secreted (RANTES), all chemokines binding to these two receptors. The CCL3/MIP-1alpha-induced shifts of intracellular calcium concentrations declined gradually to almost undetectable levels, and most conspiciuously, the chemotactic response to CCL3/MIP-1alpha, CCL4/MIP-1beta, and CCL5/RANTES was lost after infection with active influenza virus. Inactivated virus particles did not significantly alter the responsiveness induced by CCR1 and CCR5 agonists. Despite the inability of chemokine receptors to elicit migration, phosphorylation of protein kinase B was not altered in virus-infected monocytes. Thus, influenza A virus infection rapidly abolishes the functional responsiveness of monocytes and prevents an adequate response of the infected cells to chemokine stimulation.


HOXD3 enhances motility and invasiveness through the TGF-beta-dependent and -independent pathways in A549 cells.
Homeobox genes regulate sets of genes that determine cellular fates in embryonic morphogenesis and maintenance of adult tissue architecture by regulating cellular motility and cell-cell interactions. Our previous studies showed that a specific member, HOXD3, when overexpressed, upregulates integrin beta3 expression in human erythroleukemia HEL cells and lung cancer A549 cells, and enhances their motility and invasiveness. We performed a microarray study of over 7075 genes to determine the mechanisms underlying the HOXD3-enhanced motility and invasiveness in A549 cells. RT-PCR-based tracking gene analyses highlighted a set of TGF-beta-upregulated genes, which included matrix metalloproteinase-2, syndecan-1, CD44, and TGF-beta-induced 68 kDa protein. Exogenous TGF-beta also caused this pattern of upregulation in A549 cells and enhanced their migratory and invasive activity, confirming the involvement of TGF-beta signaling. However, HOXD3 reduced the expression of TGF-beta-independent genes coding for desmosomal components such as desmoglein, desmoplakin and plakoglobin which are known to suppress tumor invasion and metastasis. These results suggest that HOXD3 enhances the invasive and metastatic potential of cancer cells through the TGF-beta-dependent and -independent pathways.


Torsion of the normal uterine adnexa in premenarchal girls.
Two cases are reported of torsion of the normal uterine adnexa in premenarchal girls. In one patient, aged 3 yr, both the ovary and fallopian tube had undergone torsion. The second patient, aged 11 yr, had sustained torsion of the fallopian tube alone. This is the first reported case of torsion of the fallopian tube occurring without torsion of the ovary in a patient in this age group. The mechanisms of torsion of normal uterine adnexa are described and the operative management is discussed.