Long-term melatonin administration reduces hyperinsulinemia and improves the altered fatty-acid compositions in type 2 diabetic rats via the restoration of Delta-5 desaturase activity.
The objective of this study was to investigate the effect of long-term melatonin administration on plasma levels of triglycerides, insulin and leptin, and on the fatty-acid metabolism of plasma and hepatic lipids in type 2 diabetic rats. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes mellitus, were divided into two groups: one untreated (n=6), and one implanted with time-releasing melatonin pellets (1.1 mg/day for 30 wk) under the abdominal skin (n=6). Age-matched Long-Evans Tokushima Otsuka (LETO) rats (n=6) were used as healthy controls. The untreated diabetic rats had the increased plasma levels of triglycerides, cholesterol, insulin and leptin at 35 wk, as compared with the healthy control rats (n=6). The diabetic rats also had augmented ratios of 20:3n-6/20:4n-6 fatty acids, owing to diminished activity of Delta-5 desaturase, an insulin-permissive enzyme, in the liver. Melatonin administration to OLETF rats reduced the hypertriglyceridemia (-39%, P < 0.05), hyperinsulinemia (-33%, P < 0.01) and hyperleptinemia (-43%, P < 0.01), and restored hepatic Delta-5 desaturase activity (148%, P < 0.005). This resulted in a return to normal ratios of 20:3n-6/20:4n-6 fatty acids in plasma and hepatic lipids. There was a significant correlation (r=0.64, P < 0.005) between plasma levels of insulin and the ratios of 20:3n-6/20:4n-6 in plasma phospholipids of all rats in the three groups. Thus, subcutaneous implantation of a melatonin-releasing pellet thus resulted in improved lipid metabolism in diabetic rats, probably through restored insulin resistance.


Acute appendicitis in pregnancy and the occurrence of major intraventricular hemorrhage and periventricular leukomalacia.
Infection and endotoxemia have been associated with neurologic injury in the newborn. In addition, recent reports have noted an increased incidence of fetal neurologic injury in the presence of intrauterine infection. Three pregnancies complicated by acute appendicitis and refractory preterm labor resulting in the delivery of neonates who developed early major intraventricular hemorrhage and/or periventricular leukomalacia are described. We hypothesize that extrauterine infections like acute appendicitis may play a role in the occurrence of neonatal neurologic injury.


Saccadic latencies for achromatic and chromatic targets.
The purpose of this experiment was to compare saccadic latencies for supra-threshold achromatic and chromatic targets of equivalent contrast. Two experiments were performed. In the first experiment, subjects made saccades to horizontal and vertical chromatic (red, green, and blue) targets. The luminance of these targets was matched to the luminance of the white background. In the second experiment, subjects made saccades to horizontal and vertical achromatic targets whose luminance contrast was matched to the chromatic contrast of the targets in the first experiment using the CIE L*a*b* color space. In the first experiment, the saccadic latencies did not vary significantly (p = 0.074) for the different target colors. However, in the second experiment the mean latency for achromatic targets (268.6 ms +/- 53.1) varied significantly from the pooled latency for color targets (318.4 ms +/- 75.1).


T-cell compartment in synovial fluid of pediatric patients with JIA correlates with disease phenotype.
Juvenile idiopathic arthritis (JIA) is an autoimmune disease where T cells are key players. It can be classified into two main clinical diseases: polyarticular and pauciarticular, based on the number of joints involved. Oligoarthritis, which is considered a pauciarticular subtype since it involves up to four joints upon presentation, is further divided into persistent or extended forms based on disease progression. Here we assessed the T-cell compartment in synovial fluid obtained from 33 JIA patients with active disease and correlated the analyzed parameters with the patients' clinical characteristics. The T-cell compartment was determined by the representation of T-cell receptor (TCR) repertoires and the amount of TCR excision circles (TRECs). Patients with polyarticular disease have more a clonal pattern of their TCR repertoire. These findings were consistent in all tested TCR-Vγ consensus primers. Similarly, patients with polyarticular disease had lower TREC levels than patients with pauciarticular disease. A predictive value of TRECs may be suggested, as lower TREC levels were observed in patients in whom disease modifying anti rheumatic drugs were initiated subsequently during the follow-up. In pediatric JIA patients, we showed an alteration in the T cells from synovial fluid, which correlated with disease phenotype, assumedly secondary to enhanced proliferation, clonal TCR restriction, and reduced T-cell production, possibly reflecting a different disease or a different course of disease progression.


Laser induced breakdown spectroscopy (LIBS) as a technique to detect copper in plastic and microplastic waste.
Plastic waste is an environmental problematic, not only because of its own contamination, but also because it can act as a vector for other pollutants, particularly metals. In this work, taking advantage of the sensitivity of the LIBS technique, the presence of copper in plastics and microplastics present in a stream that receives effluents from a medium-sized city was determined. The influence of the digestion process on the collected samples was analyzed. On the other hand, copper retention in commonly used plastics submerged in stream water and in a solution prepared in the laboratory was analyzed. This study confirms that both macroplastics and microplastics collected from a stream that receives effluents from a city, can retain copper.


Zinc finger protein RP-8, the Bombyx mori ortholog of programmed cell death 2, regulates cell proliferation.
Programmed cell death 2 (PDCD2) is a highly conserved eukaryotic protein indispensable for various physiological processes such as cell proliferation, development, and apoptosis. In the present study, we identified a Zinc finger protein RP-8 from the silkworm, Bombyx mori (BmZfrp8), the ortholog of PDCD2 protein. The quantitative real-time PCR analysis revealed the ubiquitous distribution of BmZfrp8 in the different tissues; however, the gene's transcription level was highest in those of the silk gland, testis, and ovary. Additionally, the expression levels of BmZfrp8 were unequal on different days of embryonic development, and it reached the highest level on the 5th day of early development. The challenge with pathogens influenced the expression level of BmZfrp8 in both hemocyte and fat body when compared with the control. Administration of 20-hydroxyecdysone significantly enhanced the BmZfrp8 expression in hemocyte. The knock-down of BmZfrp8 by double-stranded RNA suppressed the expression of developmental pathway associated genes as well as cell cycle-associated genes. Furthermore, the RNAi treated cells also showed cell cycle arrest compared to the control group. Taken together, BmZfrp8 may have a critical biological role in of B. mori, since it regulates the expression of the developmental pathway and cell cycle-associated genes.


Degradation of n-alkanes and PAHs from the heavy crude oil using salt-tolerant bacterial consortia and analysis of their catabolic genes.
In the present study, salt-tolerant strains, Dietzia sp. HRJ2, Corynebacterium variabile HRJ4, Dietzia cinnamea HRJ5 and Bacillus tequilensis HRJ6 were isolated from the Dagang oil field, China. These strains degraded n-alkanes and polycyclic aromatic hydrocarbons (PAHs) aerobically from heavy crude oil (HCO) in an experiment at 37 °C and 140 rpm. The GC/MS investigation for degradation of different chain lengths of n-alkanes (C8-C40) by individual strains showed the highest degradation of C8-C19 (HRJ5), C20-C30 (HRJ4) and C31-C40 (HRJ5), respectively. Moreover, degradation of 16 PAHs with individual strains demonstrated that the bicyclic and pentacyclic aromatic hydrocarbons (AHs) were mostly degraded by HRJ5, tricyclic and tetracyclic AHs by HRJ6 and hexacyclic AHs by HRJ2. However, the highest degradation of total petroleum hydrocarbons (TPHs), total saturated hydrocarbons (TSH), total aromatic hydrocarbons (TAH), n-alkanes (C8-C40) and 16 PAHs was achieved by a four-membered consortium (HRJ2 + 4 + 5 + 6) within 12 days, with the predominance of HRJ4 and HRJ6 strains which was confirmed by denaturing gradient gel electrophoresis. The abundance of alkB and nah genes responsible for catabolism of n-alkanes and PAHs was quantified using the qPCR. Maximum copy numbers of genes were observed in HRJ2 + 4 + 5 + 6 consortium (gene copies l-1) 2.53 × 104 (alkB) and 3.47 × 103 (nah) at 12 days, which corresponded to higher degradation rates of petroleum hydrocarbons. The superoxide dismutase (SOD) (total SOD (T-SOD), Cu2+Zn2+-SOD), catalase (CAT) and ascorbate peroxidase (APX) activities in Allium sativum and Triticum aestivum were lower in the HRJ2 + 4 + 5 + 6-treated HCO as compared to the plantlets exposed directly to HCO. The present results revealed the effective degradation of HCO-contaminated saline medium using the microbial consortium having greater metabolic diversity.


Azo Coupling of Indoles Revisited: Synthesis of Biindolyl Photoswitches via the Azo-Coupling/C-H Functionalization Domino Approach.
When azo coupling of aryldiazonium salts with indoles was carried out in aprotic nonpolar solvent on air, a pseudo-three-component reaction has been discovered. Azo coupling is followed by a nucleophilic addition of a second indole unit to the indolium intermediate; aromatization and oxidation are achieved under air.


Effects of temperature and photoperiod on the termination of larval diapause in Lucilia sericata (Diptera: Calliphoridae).
Larvae of the blow fly, Lucilia sericata (Meigen), enter diapause in the third instar after cessation of feeding. The effects of temperature and photoperiod on the termination of diapause were examined. The diapause terminated spontaneously under the diapause-inducing condition of 20 degrees C and LD 12:12, although pupariation was not synchronous. Diapause development proceeded under a low temperature of 7.5 degrees C. Transfer to long-day conditions of LD 16:8 or to a high temperature of 25 degrees C induced prompt and synchronous pupariation. Low temperatures in winter probably play a predominant role in the termination of diapause under natural conditions.


Slow-growing large pleomorphic adenoma of ectopic lacrimal gland tissue in the upper eyelid.
A few cases of pleomorphic adenoma of an ectopic lacrimal gland involving the deep orbit and lateral canthus have been previously reported. A 75-year-old female with a slow-growing, large pleomorphic adenoma arising from ectopic lacrimal gland tissue in the left upper eyelid is described in the present case report.


Comparison of total protein and enzyme levels in successive regenerations of venom from individual coralsnakes.
Coralsnakes produce highly potent neurotoxic venoms, but little is known about variations in specific enzyme components within a species or from one replenishment of venom to the next within the same animal. Since published studies are often conducted using venom pools from multiple snakes, individual differences are masked and variations among individual snakes and between subsequent venom regenerations from the same snake have rarely been documented. This study involves the analysis and comparison of four successive venom collections from each of nine individual coralsnakes in order to detect these differences. Significant variation was found within the successive re-synthesis of venom components. Even greater differences were observed between the venoms from similar individual snakes. Since studies of variation in enzymatic activity would be significant only if they were above these normal variations, it is important to be aware of these differences. These results suggest the importance of understanding the variations present within and between individuals of the same species when interpreting the potential significance of differences found as the result of genetic, environmental or ecological factors.


Risk-adjusted female breast cancer incidence rates in the United States.
A method has been previously proposed for estimating risk-adjusted incidence rates (RAIRs) from cancer data from the Surveillance, Epidemiology, and End Results (SEER) program. Unlike conventionally reported SEER-based cancer incidence rates in the United States, but similar to the approach taken by the International Association of Cancer Registries and the International Agency for Research on Cancer, the method uses only the first primary cancer of the given site. In addition, it also adjusts for population-based cancer prevalence in order to obtain a better population-based measure of cancer risk. For most cancers multiple cancer primaries are rare and the prevalence of the disease is low. However, female breast cancer has a comparatively high risk of subsequent breast cancers and is the most prevalent cancer in women. Hence, in white women RAIRs are 3.0% lower in ages 30-39, 4.2% lower in ages 40-49, 4.0% lower in ages 50-59, 4.1% lower in ages 60-69, 3.8% lower in ages 70-79, and 4.3% lower in ages 80 years and older compared with conventional rates. Corresponding lower percentages for black women are 3.9%, 6.9%, 5.1%, 7.8%, 6.0%, and 2.2%, respectively. Age-group specific trends in breast cancer incidence rates differed between RAIRs and conventional incidence rates, increasingly so with older age. The number of cancer cases in the United States is estimated from conventional incidence rates and population estimates. In 2007, the estimated number of malignant breast cancer cases was 181,665 for white women and 20,203 for black women. The estimated number of breast cancer cases decreased by 4.8% for whites and 6.5% for blacks when based on RAIRs. RAIRs are a better measure of breast cancer risk and trends in RAIRs are better for monitoring the effect of risk factors.


The REDUCED trial: a cluster randomized trial for REDucing the utilization of CEsarean delivery for dystocia.
To reduce cesarean delivery rates in nulliparous women, guidelines for diagnosing nonprogressive labor have been developed by the National Institute of Child Health and Human Development, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine. These are mainly based on data from the Consortium for Safe Labor study. The guidelines have not been tested in a clinical trial, so the efficacy and safety of this new approach is uncertain. This study aimed to assess whether adoption of new guidelines for diagnosing nonprogressing labor would reduce cesarean delivery rates. We conducted a cluster randomized controlled trial of a knowledge translation program of the guidelines in 26 Canadian hospitals (13 control sites and 13 intervention sites). The sites included all intrapartum care sites in Alberta that perform cesarean delivery and deliver at least 70 nulliparous women annually. The baseline period started on January 1, 2015. The intervention was initiated at the first intervention site in January 2017. The follow-up period began at the first intervention site in February 2017 and lasted till February 2020. The primary outcome was the rate of cesarean delivery in nulliparous women with vertex presentation in labor at term. The secondary outcomes included spontaneous vaginal birth and maternal and neonatal safety. The main data source for the primary and secondary outcomes was the Alberta Perinatal Health Program database. The cesarean delivery rates were assessed using repeated measures mixed effects logistic regression applied to individual births. The analysis was based on 45,193 deliveries at intervention sites and 43,725 deliveries at control sites. There was no evidence of a decrease in the rate of cesarean delivery in association with the intervention (baseline-adjusted odds ratio, 0.94; 95% confidence interval [0.85-1.05]; P=.259). The rate of spontaneous vaginal delivery increased slightly (baseline-adjusted odds ratio, 1.10; 95% confidence interval, [1.01-1.18]; P=.024). We did not observe any differences in adverse maternal or neonatal outcomes. Cesarean delivery rates in nulliparous women were not reduced by the application of recent guidelines for the diagnosis of nonprogressive labor. Spontaneous vaginal delivery-a secondary outcome-was increased in the intervention group. The intervention appears to be safe.


The role of gamma-carboxyglutamyl residues in the positive cooperative binding of Ca2+ to blood coagulation factor X.
1. The calcium binding properties of factor X and its analogous decarboxyprotein have been compared with the aid of flow rate dialysis and ultraviolet difference spectroscopy. 2. Factor X binds approx. 20 mol of calcium per mol of protein. The first four sites exhibit positive cooperativity. 3. Changes in the ultraviolet difference spectrum when Ca2+ is bound suggest a conformational change. 4. In decarboxyfactor X low affinity of Ca2+ and no ligand-induced conformational change was observed. It is concluded that the presence of gamma-carboxyglutamate residues is a prerequisite for positive cooperative Ca2+ binding.


Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia.
Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN. In vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans. In a mouse model of FTD-GRN, the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers. These findings support the development of latozinemab for the treatment of FTD-GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial. Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204 .


Mycotoxigenic fungi and mycotoxins associated with stored maize from different regions of Lesotho.
Samples of stored maize from villages located in five different agroecological zones (southern lowlands, northern lowlands, Senqu river valley, foothills and mountains) of Lesotho were collected in 2009/10 and 2010/11 and assessed for contamination with toxigenic fungi. The water activity of all samples collected during the two seasons was <0.70. The total fungal populations of the maize from different regions in the two seasons was not significantly different (p > 0.05). Fusarium verticillioides, F. proliferatum and F. subglutinans predominated in different regions in both seasons based on molecular analyses. In the 2009/10 season, the isolates of these species all produced FB1, while in the 2010/11 season, very few produced FB1. A. flavus isolates (2009/10) were recovered from mountains and Senqu river valley samples while the 2010/11 isolates were predominantly from the foothills and northern lowlands. The mountain isolates of Aspergillus section Flavi produced the highest levels of AFB1 (20 mg kg(-1)). Aspergillus parasiticus was only isolated from the foothills, Senqu river valley and southern lowlands samples, and the AFB1 levels produced ranged from 'none detected' to 3.5 mg kg(-1). The Aspergillus ochraceous isolates were least frequently encountered in both seasons. In the 2009/10 season, the isolates from the northern lowlands produced ochratoxin A (OTA) in culture. No isolates of A. niger from different regions in both seasons produced any OTA. Multi-mycotoxin analyses of the maize samples were done for a range of mycotoxins. At least one sample from each region in both seasons was FB1-positive. FB1 levels for 2010/11 samples (7-936 μg kg(-1)) were higher than in the 2009/10 season (2-3 μg kg(-1)). In both seasons, the mountains registered the highest levels of FB1. Deoxynivalenol (DON) was recovered from all the samples analysed, with the highest mean contamination of 1,469 μg kg(-1) in samples from the northern lowlands. Moniliformin (MON) was detected from all agroecological zones in the two seasons (5-320 μg kg(-1) in 2009/10; 15-1,205 μg kg(-1) in 2010/11). Emerging toxins such as fusaproliferin (FUS) and beauvericin (BEA) were also detected. OTA was not detected in any of the samples analysed. Only one 2009/10 sample in the Senqu river valley was positive for AFB1. This is the first report on toxigenic fungi and multi-mycotoxin contamination of maize samples from subsistence farmers' stores in different agroecological zones of Lesotho.


Tryptophan catabolites in mesenteric lymph may contribute to pancreatitis-associated organ failure.
Multiple organ failure (MOF) is the key determinant of mortality in acute pancreatitis (AP). Mesenteric lymph cytotoxicity contributes to organ failure in experimental models of systemic inflammation. The aim of this study was to evaluate the mesenteric lymph pathway and the lymph injury proteome in experimental AP-associated MOF, and to test the hypothesis that immunoregulatory tryptophan catabolites contribute to mesenteric lymph cytotoxicity. Using an experimental model of AP in rats, the humoral component of mesenteric lymph in AP was compared with that from sham-operated control animals, using in vitro and in vivo cytotoxicity assays, high-throughput proteomics and high-performance liquid chromatography. The experimental findings were corroborated in a cohort of 34 patients with AP. Compared with biologically inactive lymph from sham-operated rats, mesenteric lymph in AP became cytotoxic 3 h after induction. Hierarchical clustering of lymph proteomic mass spectra predicted the biological behaviour of lymph. Levels of the immunoregulatory tryptophan catabolite, 3-hydroxykynurenine, were increased in cytotoxic lymph and re-created cytotoxicity in vitro. In humans with AP, plasma kynurenine concentrations correlated in real time with MOF scores and preceded a requirement for mechanical ventilation and haemodialysis. These results support the concept that mesenteric lymph-borne kynurenines may contribute to pancreatitis-associated MOF.


A novel and convenient self-drying system for bacterial preservation.
An effective microbial preservation technology for the long-term storage of viable prokaryotic cells is described. The method combines an almost instantaneous drying step with minimal stress to the cells during drying to maximize survival on rehydration. This is achieved by contact of a microlitre aliquot of a bacterial suspension with a novel, pre-dried activated charcoal cloth based matrix contained within a re-sealable system that can then be stored. The simple methodology completely circumvents the requirement for further drying or preparation. Using this method, a standard laboratory Escherichia coli strain was successfully revived following 390 days storage at 4, 20 and 30 degrees C. Data obtained yielded approximately 20%, 6% and 0.1% viable organisms at the aforementioned temperatures, respectively, following initial inoculations of 1.1 x 10(8)/microl cells. While these figures represent a significant viability loss, there is sufficient recovery of microorganisms required for maintaining culture collections.


The diversity of flower flies (Diptera: syrphidae) in Colombia and their neotropical distribution.
In Colombia, like most Neotropical countries, faunistic studies on flower flies have been occasional and most of them have been primarily focused on taxonomy. Colombia is the second-most species-rich country in flower fly diversity in the Neotropics after Brazil, and has one of the highest numbers of species per unit area (2.49 per 10,000 km²), based on a review of literature and national collections. Including new data presented here, a total of 47 genera and 300 species are recorded in Colombia. The genera Scaeva Fabricius and Lycastrirhyncha Bigot, as well as 101 species are recorded here for the first time. The altitudinal range and the distribution of the flower fly genera in Colombia are presented. A preliminary comparison of the fauna of Colombia with that of other Neotropical countries is given. A historical perspective is also provided in order to illustrate how Colombian Syrphidae knowledge has progressed over the last 168 years. Information presented here will be useful for ongoing and future biodiversity research as well as conservation projects on Syrphidae in the Neotropical region.


Species richness of Macrolepidoptera on Finnish deciduous trees and shrubs.
Species richness of Macrolepidoptera on Finnish trees and shrubs was analysed by means of stepwise regression analysis. The explaining variables were plant frequency, geographical range, plant height, number of relatives and leaf size.Total frequency of the host plant, which correlated strongly with range, explained 57% of the observed variance of lepidopteran species richness on deciduous trees and shrubs. Height of plant and number of relatives explained significantly the residual variation and altogether these three variables explained 71% of the variance of species richness.Analyses at the plant genus level gave similar results and frequency, height and number of relatives explained 78% of the variance of species richness of Macrolepidoptera on deciduous plant genera.When conifers were included in the analysis leaf size also becomes a significant variable. Leaf size can, however, act as a dummy variable which effectively distinguishes conifers from deciduous trees.The validity of different models explaining herbivore species richness on plants is discussed. The results of this study favoured more than earlier studies the importance of relatedness of host plants as a factor which determines the species richness of herbivores.


[Value of dual-energy computed tomography for detection of left atrial appendage thrombus].
Contrast-enhanced computed tomography (CT) is a convenient method to visualize left atrial appendage (LAA) thrombi. We determined whether diagnostic accuracy improves by including dual-energy as compared to transesophageal echocardiography (TEE). Furthermore, the influence of protocol parameters on radiation dose were quantified. Patients were assigned to the different CT protocols. All CTs were assessed qualitatively for presence of LAA thrombi and dual-energy CT scans quantitatively for iodine concentration. TEE was assessed qualitatively for the presence of thrombi. Of 32 enrolled patients, 6 had a thrombus in TEE. Qualitative CT assessment yielded 83% sensitivity and 88% specificity. In the 26 patients who underwent dual-energy CT, median iodine concentration was 8.6 mg/cm3 and significantly lower in patients with than without LAA thrombi ; furthermore, it provided value for detecting LAA thrombi (AUC: 0.950 vs 0.867 for combined vs. only qualitative assessment, p = 0.04). The median radiation dose was 1.83 mSv; independently lower in scanning only LAA and with prospective gating , while arrhythmia and dual-energy did not contribute independently. CT provides good diagnostic accuracy for detecting LAA thrombi, which can further be improved if iodine density measurements by dual-energy are incorporated. With an optimized protocol, reasonably low radiation dose can be achieved.


The cytoplasmic plaque of tight junctions: a scaffolding and signalling center.
The region of cytoplasm underlying the tight junction (TJ) contains several multimolecular protein complexes, which are involved in scaffolding of membrane proteins, regulation of cytoskeletal organization, establishment of polarity, and signalling to and from the nucleus. In this review, we summarize some of the most recent advances in understanding the identity of these proteins, their domain organization, their protein interactions, and their functions in vertebrate organisms. Analysis of knockdown and knockout model systems shows that several TJ proteins are essential for the formation of epithelial tissues and early embryonic development, whereas others appear to have redundant functions.


Image-guided lung tumor ablation: principle, technique, and current status.
Image-guided tumor ablation for lung malignancies has emerged as a treatment modality for medically inoperable patients. Overall, image-guided lung tumor ablation is a minimally invasive procedure that has an acceptable safety profile and less impact on lung function. This is important for patients with poor pulmonary and/or cardiac functions or with multiple comorbidities, which prevent them from undergoing surgery, chemotherapy, and radiation therapy. Herein, we review the principle, techniques, clinical application, and patient outcomes of image-guided lung tumor ablation.


Molecular pathogenesis involved in human idiopathic pulmonary fibrosis based on an integrated microRNA‑mRNA interaction network.
Idiopathic pulmonary fibrosis (IPF) is considered to be an ailment of the lungs that cannot be cured, wherein the lung tissues are characterized by increased thickness and stiffness, and/or scars. Despite the fact that extensive success has been achieved regarding the molecular diagnostics and pathobiology, the basic pathogenesis associated with IPF has not yet been fully elucidated and requires further clarification. In the current research, the changes in microRNA (miRNA) and mRNA expression in IPF were investigated through an integrative network technique. The authentic miRNA and mRNA expression profiling datasets were downloaded from Gene Expression Omnibus, followed by identification of differentially expressed miRNAs and mRNAs with use of the Significance Analysis of Microarrays algorithm. Expansion of the molecular targets associated with miRNAs was performed with the use of CyTargetLinker in Cytoscape, which was succeeded by validation with the use of mRNA array expression profiling. The incorporated miRNA‑mRNA network covered 27 genes, in addition to 22 miRNAs that were associated with IPF development. As revealed by the functional enrichment analysis, the cytokine‑cytokine receptor interaction and glycine, serine and threonine metabolism signalling pathways were extensively associated with IPF development. Overall, the present incorporated network illustrated the key link between miRNA and genes in IPF; in particular, it was elucidated that miR‑409‑5p and has‑miR‑376c, together with their target genes (C‑C motif chemokine ligand 20 and oncostatin M), are likely candidates involved in the promotion of IPF initiation and progression.


Strategy for high-yield astaxanthin recovery directly from wet Haematococcus pluvialis without pretreatment.
A novel integrated extraction technique for high recovery of natural astaxanthin from wet encysted Haematococcus pluvialis (H. pluvialis) is demonstrated. The technique can be used to effectively disrupt the cell wall and perform extraction in a one-pot system without a high-energy, cost intensive pre-drying step. The most suitable green solvent was researched in terms of high extraction yield and astaxanthin recovery. Moreover, an optimized condition for the selected green solvents was determined by varying process parameters, viz., the ball milling speed (100-300 rpm) and time (5-30 min). A high recovery of astaxanthin directly from wet H. pluvialis (30.6 mg/g based on its dry mass) and a high extraction yield (58.2 wt%) were achieved using ethyl acetate at 200 rpm after 30 min. Therefore, compared to its counterparts, the biphasic solvent system plays a key role in achieving high extraction yield and astaxanthin recovery from wet H. pluvialis.


Group B streptococci (GBS) strains evading molecular diagnostics showed novel chromosomal deletions encompassing the CAMP-factor (cfb) encoding gene.
A highly conserved fragment adjacent to the cfb gene encoding the CAMP factor is the target of PCR-based molecular diagnostic systems for the identification of S. agalactiae (group B streptococci (GBS)). Six PCR-negative, culture-positive GBS strains were whole genome sequenced to assess why they escaped molecular diagnostics. GBS strains did not constitute a clonal cluster and presented variably sized chromosomal deletions (from 7 to 33 kb) which always included the cfb gene, a finding never described before. GBS strains that escape molecular diagnostics are considered rare; however, they can cause false-negative results using molecular diagnostics alone, affecting medical decisions.


Regional Variations and Trends in Ambient Noise: Examples from Australian Waters.
Studies of ambient noise south of Australia show higher levels at low frequencies in the deep water off the continental shelf compared with locations on the shelf. The difference arises because of differences in transmission loss. Marine animals would experience significantly different noise levels and directionality in the two regions and while crossing the boundary, provide positional information. Opportunities for long-range, low-frequency communication by animals would be significantly limited by the higher background noise in the open ocean. Measures of long-term sea noise trends highlight the influence of biological sources and the importance of local sound transmission regimens.


Retroviral gag and DNA endonuclease coding sequences in IgE-binding factor gene.
Immunoglobulin-binding factors are known to regulate the synthesis of B-cell-derived immunoglobulin heavy-chain isotypes. Cloning and nucleotide sequence determination of complementary DNA encoding rodent IgE-binding factors (IgE-BF) revealed that messenger RNA encodes a glycoprotein of 557 amino acids which is expressed as a precursor of relative molecular mass (Mr) 60,000 (60K) in COS7 monkey cells. We report here that the 3' two-thirds of the IgE-BF coding sequence shows a surprising homology (72%) at the DNA level with coding sequences of the gag and pol (DNA endonuclease) genes of the Syrian hamster intracisternal A particle (IAP H18), an endogenous retrovirus. This marked homology demonstrates that the rodent gene encoding IgE-BF is a hybrid gene which evolved very recently by integrating genes of viral origin, and that the encoded polypeptide comprises three separate domains: an IgE-BF domain and retrovirus-derived gag and DNA endonuclease-like domains. This may represent the first report of a cellular gene containing a virus-derived coding sequence.


Survival of Dicor glass-ceramic dental restorations over 14 years: Part I. Survival of Dicor complete coverage restorations and effect of internal surface acid etching, tooth position, gender, and age.
There are no long-term data on Dicor glass-ceramic restoration survival in the human oral cavity and the effect that different technical and clinical variables have on survival. This prospective study examined the relationship of different clinical parameters on the survival of Dicor glass-ceramic restorations in the human oral cavity. A total of 417 subjects (from 17 to 91 years of age) participated. All subjects required single unit fixed prosthodontics in any area of the mouth and/or 3-unit fixed partial dentures or cantilevered anterior restorations. They were offered the option of a gold or conventional metal-ceramic restoration, or a Dicor restoration with potentially improved esthetic results, better wear characteristics, and diminished oral plaque accumulation. Overall survival of the restorations was determined and the effect of various clinical parameters evaluated with Kaplan-Meier survival curves. Log rank tests were used to determine statistically significant differences among parameters. For the 1444 units placed, 188 failures were recorded. Total time at risk for the units was 7319 years providing an estimated risk of 2.45% per year. Probabilities of survival of "typical" acid-etched Dicor and nonacid-etched Dicor restorations were 76% and 50%, respectively, at 14.1 years (P <.001). Probabilities of survival of typical acid-etched and nonacid-etched Dicor complete coverage restorations were virtually identical to those observed in the full data set. There was a 2.2 times greater risk of failure associated with the use of nonacid-etched Dicor complete coverage than acid-etched restorations (P <.01). Complete coverage restoration survival was highest in the incisor region and decreased to the molars in both arches. Second molars showed the highest failure rate. No complete coverage restorations failed on lateral incisors during the entire study. Probability of survival of a typical acid-etched Dicor complete coverage restoration in male subjects was 71%, and 75% for female subjects at 14.1 years (P <.01). The major difference appeared to be due to a greater failure rate in the maxillary arch of the male. Survivor functions of acid-etched Dicor complete coverage restorations for subjects in <33 years, 33 to 52 years, and 52 years age groups were 88% at 9 years, 62% at 14 years, and 82% at 14 years, respectively. Dicor restorations can survive successfully over time with certain reservations. Long-term survival improved significantly when restorations were acid-etched before luting. Complete coverage restoration failures per year decreased from molars to incisors in both arches, suggesting that complete coverage restorations on molars represented a serious risk. No Dicor complete coverage restoration on lateral incisors failed during the study. Restorations failed less often in female than male subjects.


5-Azacytidine is able to induce the conversion of teratocarcinoma-derived mesenchymal cells into epithelia cells.
The inhibitor of DNA-methylation, 5-azacytidine (5- AzaC ) induced the appearance of cytokeratin-containing cells in several mesenchymal cell lines such as teratocarcinoma-derived fibroblasts, preadipocytes and myoblasts, NIH-3T3 fibroblasts and human embryonic fibroblasts. At optimal 5- AzaC concentrations the proportion of such cells was in the range of 10(-1) compared with 10(-6) -10(-4) in non-treated cultures. Dose-response curves indicated that the induction of cytokeratin was the result of an interaction of the drug with few targets. Stable, mature, keratinocyte cell lines, as well as lines of myoblasts and astrocytes, could be isolated from a teratocarcinoma-derived preadipocyte line, showing that 5- AzaC is able to provoke a wide range of complete phenotypic conversions. In these cell lines, the intermediate filaments corresponded to the morphological phenotype. Altogether, the results suggest that 5- AzaC preferentially activates certain genes.


Disability, residential environment and social participation: factors influencing daily mobility of persons living in residential care facilities in two regions of France.
Despite the context of individualization of public policies and promotion of independent living, residential care facilities (RCFs) (called "établissements medico-sociaux" in France) still represent the main system used by disabled people. Through a study of their daily mobility, this article proposes a geographical approach to the examination of factors influencing the social participation of disabled persons with motor impairments who live in residential care facilities. The data were collected in three stages from several sources. We first carried out 24 semi-directive interviews among supervisory staff in all the institutions in two regions of France (Greater Paris and Upper Normandy) to better understand the nature of services offered by medico-social facilities. We next did field work in greater detail in 10 of these institutions. We selected residents by random sampling. These first stages then allowed us to study the mobility of residents and record their perceptions. We conducted participant observation and interviews with 81 disabled residents within the 10 RCF. Data analysis enabled consideration not only of the role of the residential environment in people's daily mobility, but the role of the institutions as well. We identified three typical profiles of mobility practices depending on the facilities: "the islanders", living in isolated facilities far from public transportation, or in so-called "difficult" neighborhoods; people who alternate individual and group mobility in a more or less large area; and "the navigators" who have high mobility over a very large area, often living in facilities located in urban areas. The study also enabled an analysis of the obstacles and facilitators inside and outside the residential facilities. These place restrictions on social participation by disabled adults. However, possibilities for individual negotiation may enable bypassing some obstacles. The three ideal-type profiles of mobility analyzed constitute adaptations to the environment by residents and the institution. The research techniques used and the presentation of data (in the form of diagrams) enabled a better understanding of the mobility of severely disabled adults living in an institution, a population that is rarely studied.


The effect of extralumenal safety wires on ureteral injury and insertion force of ureteral access sheaths: evaluation using an ex vivo porcine model.
To evaluate the effect that a safety wire (SW) had on insertion force and direct ureteral trauma using ureteral access sheaths (UAS) in an ex vivo porcine model. UASs were advance into 20 fresh ex vivo porcine kidney-ureters, either with or without SWs. The average and max force of insertion were recorded. Retrograde saline injection was used to identify the presence of lacerations. For SW vs no SW, the mean insertion force (1.79 vs 0.67, P = .0003, respectively) and max insertion force (2.29 kg vs 1.00, P = .0007) was greater in the SW group. There were 9 lacerations, 6 of which were partial and 3 complete. Of the partial injuries, 2 were in the no SW group and 4 were in the SW group. Of the complete lacerations, 2 occurred in the no SW group and 1 in the SW group. However, there was no significant difference in the total number of lacerations (P = 1.00), the number of partial lacerations (P = .628), or the number of complete lacerations (P = 1.00) between the 2 groups. The use of an SW significantly increases the force required to insert a UAS; however, it does not appear to affect the force or the degree of ureteral injury.


Associations of Endothelin Polymorphisms and Aneurysm Size at Time of Rupture.
Aneurysm size is an important risk factor for aneurysm rupture. The pathophysiologic mechanisms underlying aneurysm growth remain poorly understood. Endothelin signaling is critical for cerebrovascular blood flow regulation. The influence of endothelin single nucleotide polymorphisms (SNPs) on aneurysm size at the time of rupture has not been previously investigated. Eight common endothelin SNPs were assessed using blood samples from aneurysmal subarachnoid hemorrhage (aSAH) patients enrolled in the Cerebral Aneurysm Renin Angiotensin System study, a prospective, 2-center study that enrolled aSAH patients and controls in the United States from 2012-2015. Genetic evaluation was performed using 5'exonnuclease (Taqman) genotyping assays. Associations of endothelin SNPs and aneurysm size were analyzed. One-hundred and forty-nine blood samples from aSAH patients were available for analysis. There was a dominant effect of the G allele of the endothelin receptor type A (EDNRA) SNP rs5335 on aneurysm size ≥7 mm (odds ratio = 2.740, 95% confidence interval 1.039-7.228, P = 0.042) along with associations with race and presence of additional aneurysms. The other endothelin SNPs were not associated with aneurysm size. The EDNRA SNP rs5335 was independently associated with aneurysms ≥7 mm in size at the time of rupture. Patients with cerebral aneurysms also carrying the G allele of EDNRA SNP rs5335 may develop larger aneurysms before rupture.


Very high proportion of disaturated molecular species in rat platelet diacyl-glycerophosphocholine: involvement of CoA-dependent transacylation reactions.
The molecular species composition of rat platelet diacyl-glycerophosphocholine (GPC) was investigated by reverse-phase HPLC and by mass spectrometry. The two methods gave the same very high proportion of fully saturated phospholipids, the 16:0-16:0 and 16:0-18:0 species representing together about 40% of the overall molecular species. [14C]Palmitoyllyso-GPC was found to be acylated by resting platelets in equal amounts into 16:0-16:0 and into 16:0-20:4 species. The acylation rate of this lysophospholipid was increased by 3-fold and 14-fold when platelets were stimulated for 10 min with thrombin and the ionophore A23187, respectively. Essentially the same two molecular species were synthesized upon stimulation but with a higher preference for arachidonate than for palmitate. We investigated the mechanisms responsible for the incorporation of palmitate and arachidonate by examining the enzymatic acylation of [14C]palmitoyllyso-GPC by platelet homogenates. The percentage of the various molecular species formed when CoA, ATP, and Mg2+ were added excludes the CoA, ATP-dependent pathway as being involved in the acylation reactions previously observed. In the absence of ATP, CoA-independent transacylations appear to play a crucial role in the synthesis of the 16:0-20:4 species whereas the addition of CoA greatly favored dipalmitoyl-GPC synthesis. The involvement of CoA-dependent mechanisms in the synthesis of dipalmitoyl-GPC was demonstrated as follows: (i) the labeling in the sn-2 position of the dipalmitoyl-GPC synthesized in the presence of CoA was not modified when free unlabeled palmitic acid was added to the incubation medium and (ii) platelet homogenates were unable to esterify lysolecithin with added labeled palmitic acid in the presence of CoA only.


Reviving a 60 million year old LINE-1 element.
Mobile elements have significantly impacted genome structure of most organisms. The continued activity of the mobile element, LINE-1 (L1), through time has contributed to the accumulation of over half a million L1 copies in the human genome. Most copies in the human genome belong to evolutionary older extinct L1s. Here we apply our previous published approach to "revive" the extinct L1 PA13A; an L1 family that was active about 60 million year ago (mya). The reconstructed L1PA13A is retrocompentent in culture, but shows a significantly lower level of activity in HeLa cells when compared to the modern L1 element (L1PA1) and a 40 million year old L1PA8. L1 elements code for two proteins (ORF1p and ORF2p) that are necessary for retrotransposition. Using PA13A-PA1 and PA13A-PA8 L1 chimeric elements, we determined that both the ORF1p and ORF2p contribute to the observed decrease in retrotransposition efficiency of L1PA13A. The lower retrotransposition rate of L1PA13A is consistent in both human and rodent cell lines. However, in rodent cells, the chimeric element L1PA:1-13 containing the modern L1PA1 ORF1p shows a recovery in the retrotransposition rate, suggestive that the L1PA13A ORF2p efficiently drives retrotransposition in these cells. The functionality of the L1PA13A ORF2p was further confirmed by demonstrating its ability to drive Alu retrotransposition in rodent cells. The variation in L1PA13A retrotransposition rates observed between rodent and human cells are suggestive that cellular environment significantly affects retrotransposition efficiency, which may be mediated through an interaction with ORF1p. Based on these observations, we speculate that the observed differences between cell lines may reflect an evolutionary adaptation of the L1 element to its host cell.


Photosensitive tyrosine analogues unravel site-dependent phosphorylation in TrkA initiated MAPK/ERK signaling.
Tyrosine kinase A (TrkA) is a membrane receptor which, upon ligand binding, activates several pathways including MAPK/ERK signaling, implicated in a spectrum of human pathologies; thus, TrkA is an emerging therapeutic target in treatment of neuronal diseases and cancer. However, mechanistic insights into TrKA signaling are lacking due to lack of site-dependent phosphorylation control. Here we engineer two light-sensitive tyrosine analogues, namely p-azido-L-phenylalanine (AzF) and the caged-tyrosine (ONB), through amber codon suppression to optically manipulate the phosphorylation state of individual intracellular tyrosines in TrkA. We identify TrkA-AzF and ONB mutants, which can activate the ERK pathway in the absence of NGF ligand binding through light control. Our results not only reveal how TrkA site-dependent phosphorylation controls the defined signaling process, but also extend the genetic code expansion technology to enable regulation of receptor-type kinase activation by optical control at the precision of a single phosphorylation site. It paves the way for comprehensive analysis of kinase-associated pathways as well as screening of compounds intervening in a site-directed phosphorylation pathway for targeted therapy.


Late preterm birth: management dilemmas.
In summary, late preterm birth results from spontaneous, indicated, and sometime elective indications. The burden of prematurity can be decreased if elective late preterm delivery is eliminated. While recent recommendations from the NICHD/SMFM workshop on timing of late preterm and early term birth have helped to guide management, the authors acknowledge that most of their guidelines are based on grade B or C evidence. Certain conditions absolutely warrant late preterm delivery; however, the clinician should weigh the risks of iatrogenic prematurity with the benefits of delivery for maternal or fetal indication when considering intervention for this cohort.


Predicting and preventing acute kidney injury after cardiac surgery.
Acute kidney injury (AKI) after cardiac surgery is associated with significant morbidity and mortality. Despite the proliferation of predictive clinical scoring models of renal risk after cardiac surgery, limitations in preventing AKI through the use of pharmacological agents remain. Here we review the evolution of predictive models of renal risk after cardiac surgery, and highlight the important gains made in preventing its occurrence. Simple risk indices predicting AKI after cardiac surgery have been developed and can now be readily applied clinically. However, studies focusing on preventing AKI after surgery have yet to demonstrate any consistent renoprotective effect. Clinical scoring systems predicting AKI risk after cardiac surgery are available and should be employed in the preoperative assessment. Elucidation of beneficial preventive strategies of AKI after cardiac surgery requires ongoing research.


Dietary methylmercury and vegetable oil affects brain lipid composition in Atlantic salmon (Salmo salar L.).
The interaction between methylmercury (MeHg) and marine fatty acids is of great interest in risk benefit assessments, and is increasingly important also in fish nutrition when fish oil is replaced with vegetable oils. To assess the effects of replacing fish oil (high dietary n-3/n-6 ratio) by soybean oil (low dietary n-3/n-6 ratio) in combination with MeHg, Atlantic salmon (Salmo salar L.) were fed experimental diets (fish oil (FO) or vegetable oil (VO) based, with or without the addition of MeHg) for 3 months. As expected replacing dietary fish oil by soybean oil had greater effect on the fatty acid composition in white muscle compared to brain. In brain, the relative levels of 18:2 n-6 and 20:4 n-6 increased in all lipid classes in fish fed the VO based diets whereas the levels of marine omega-3 PUFA (polyunsaturated fatty acid) were unaffected. Different dietary lipid sources did not affect the accumulation of mercury in brain nor muscle. However, exposure to dietary MeHg resulted in decreased levels of 20:4 n-6 (arachidonic acid; ARA) in phosphatidylinositol in brain of VO fed fish. The decreased amounts of ARA in VO fish is suggested to be caused by interaction between high n-6 level and MeHg.


Dogs lacking Apolipoprotein E show advanced atherosclerosis leading to apparent clinical complications.
Atherosclerotic cardiovascular disease resulting from dysregulated lipid metabolism is the leading cause of morbidity and mortality worldwide. Apolipoprotein E (ApoE) plays a critical role in cholesterol metabolism. Knockouts in lipid-metabolizing proteins including ApoE in multiple model organisms such as mice and rats exhibiting elevated levels of cholesterol have been widely used for dissecting the pathology of atherosclerosis, but few of these animal models exhibit advanced atherosclerotic plaques leading to ischemia-induced clinical symptoms, limiting their use for translational studies. Here we report hypercholesterolemia and severe atherosclerosis characterized by stenosis and occlusion of arteries, together with clinical manifestations of stroke and gangrene, in ApoE knockout dogs generated by CRISPR/Cas9 and cloned by somatic cell nuclear transfer technologies. Importantly, the hypercholesterolemia and atherosclerotic complications in F0 mutants are recapitulated in their offspring. As the ApoE-associated atherosclerosis and clinical manifestations in mutant dogs are more similar to that in human patients compared with those in other animal models, these mutant dogs will be invaluable in developing and evaluating new therapies, including endovascular procedures, against atherosclerosis and related disorders.


Comparison of single-surgeon series of transperitoneal laparoendoscopic single-site surgery and standard laparoscopic adrenalectomy.
To assess the feasibility, safety, and efficacy of transperitoneal laparoendoscopic single-site (LESS) adrenalectomy and determine whether it shows any objective advantage compared with standard laparoscopy. From August 2009 to May 2011, 13 transperitoneal LESS adrenalectomies were performed through a 2-3-cm skin incision using the TriPort access system. This cohort was compared with a contemporary 1:2 matched-pair group of 26 patients undergoing standard laparoscopic adrenalectomy by the same urologist. The perioperative outcomes, including cosmetic satisfaction scores, were statistically analyzed. The 2 groups were comparable with respect to patient demographics, estimated blood loss, and postoperative hospitalization (P > .05). The LESS procedures had a longer mean operative time (148.5 vs 112.9 minutes, P = .032) but a significantly lower postoperative visual analog pain scale score (2.3 vs 3.7, P = .001), fewer patients requiring analgesics (30.8% vs 73.1%, P = .011), and an earlier resumption of oral intake (21.6 vs 26.0 hours, P = .002). The mean length of the scar in the LESS group was much smaller (2.3 vs 5.9 cm, P < .0001) with a statistically significant greater mean cosmetic satisfaction score (9.5 vs 9.1, P = .042). The perioperative outcomes of transperitoneal LESS adrenalectomy for small adrenal tumors were comparable to those with the standard laparoscopic approach. It also provides better postoperative pain control, faster recovery of bowel function, and better cosmetic satisfaction than standard laparoscopy, albeit with a longer operative time.


Is misonidazole binding to mouse tissues a measure of cellular pO2?
Misonidazole (MISO), a hypoxic cell radiosensitizer, forms covalently-linked adducts to cellular molecules as a result of bioreductive metabolism, a process which is strongly dependent upon oxygen concentration. MISO binding to liver tissue taken from air-breathing mice was three to five times greater than binding to other normal tissues. The relative binding of [14C]MISO to various mouse tissue cubes in vitro was measured by autoradiography as a function of defined oxygen concentrations, and standard curves (binding rate vs oxygen concentration) were generated. The oxygen concentration for half-maximum binding as well as the maximum and minimum binding rates (grains per 100 micron 2) observed for liver tissue were not significantly different from those measured for brain or heart tissue. These results, along with previously published data on MISO binding to isolated hepatocytes in vitro, suggest that the elevated binding to liver in vivo may result, in part, from the organ existing at a significantly lower pO2 than other normal tissues. They also suggest that this drug adduct procedure could be developed as a sensitive method for the quantitative measurement of tissue pO2 at the cellular level.


Seroprevalence and molecular diagnosis of Toxoplasma gondii infection among blood donors in southern Iran.
Toxoplasma gondii is a protozoan parasite which can be transmitted to human through a variety of routes including blood transfusion. This cross sectional study aimed to evaluate the seroprevalence of Toxoplasma infection and related epidemiological features among healthy blood donors. A total of 1,480 healthy blood donors from five blood service centers in Fars province were analyzed for anti-Toxoplasma antibodies. Blood samples were tested for anti-T. gondii IgG and IgM antibodies by enzyme immunoassay. IgM-positive samples were also tested for the presence of Toxoplasma DNA by Polymerase Chain Reaction (PCR). Demographic characteristics of participants were also recorded during samples collection. Anti T. gondii antibodies were detected in sera of 286 out of 1,480 blood donors corresponding to an overall seroprevalence of 19.3% in this population. From these, 182 (12.3%) were seropositive only for IgG, 81 (5.47%) were seropositive only for IgM and 23 (1.6%) were positive for both IgG and IgM. PCR detected active parasitemia in two (1.9%) of the IgM-positive subjects. Age, place of residence and level of education were statistically significant (p < 0.05) with seropositivity to Toxoplasma. Our results highlighted that asymptomatic blood donors, especially those with active parasitemia, may constitute a significant risk of transmitting toxoplasmosis to susceptible recipients.


Serum levels of biomarkers of bone and cartilage destruction and new bone formation in different cohorts of patients with axial spondyloarthritis with and without tumor necrosis factor-alpha blocker treatment.
Recent data about radiographic progression during treatment with tumor necrosis factor-alpha (TNF-alpha) blocker agents in patients with ankylosing spondylitis (AS) have prompted an intensive discussion about the link between inflammation/bone destruction and new bone formation and the order of events. Therefore, we analysed parameters of cartilage degradation, neoangiogenesis, and new bone formation in different cohorts of patients with axial spondyloarthritis with and without treatment with TNF-alpha blocker agents. TNF-alpha blocker-naïve AS patients were investigated for serum levels of metalloproteinase-3 (MMP-3) (n = 71), vasoendothelial growth factor (VEGF) (n = 50), and bone-specific alkaline phosphatase (BALP) (n = 71) at baseline and after 1 and 2 years. This was compared with 34 adalimumab-treated patients with axial spondyloarthritis (22 AS and 12 non-radiographic axial spondyloarthritis patients) before and after 36 to 52 weeks of treatment. There were no significant changes in serum levels of MMP-3 (P > 0.05), VEGF (P > 0.05), and BALP (P > 0.05) in a large cohort of TNF-alpha blocker-naïve AS patients followed for 2 years. In contrast, adalimumab-treated spondyloarthritis (AS and non-radiographic axial spondyloarthritis) patients had a significant decrease of VEGF (P < 0.001) and MMP-3 (P = 0.022) after 36 to 52 weeks of therapy. Most interestingly, the level of BALP increased significantly after 36 to 52 weeks of therapy (P < 0.001). A decrease in MMP-3 serum levels correlated significantly to an increase of BALP (r = -0.398, P = 0.02). In the case of VEGF, there was a negative correlation without significance (r = -0.214, P > 0.05). Rising levels of BALP and the negative correlation between MMP-3 and BALP in spondyloarthritis patients with TNF-alpha blocker treatment indicate that new bone formation in AS occurs if inflammation is successfully treated and might be part of a healing process.


Regularized regression method for genome-wide association studies.
We use a novel penalized approach for genome-wide association study that accounts for the linkage disequilibrium between adjacent markers. This method uses a penalty on the difference of the genetic effect at adjacent single-nucleotide polymorphisms and combines it with the minimax concave penalty, which has been shown to be superior to the least absolute shrinkage and selection operator (LASSO) in terms of estimator bias and selection consistency. Our method is implemented using a coordinate descent algorithm. The value of the tuning parameters is determined by extended Bayesian information criteria. The leave-one-out method is used to compute p-values of selected single-nucleotide polymorphisms. Its applicability to a simulated data from Genetic Analysis Workshop 17 replication one is illustrated. Our method selects three SNPs (C13S522, C13S523, and C13S524), whereas the LASSO method selects two SNPs (C13S522 and C13S523).


The Effects of Email Performance-Based Feedback on Teacher Candidate Implementation of a Multiple Stimulus Without Replacement Preference Assessment.
The purpose of this study was to evaluate the effects of performance-based feedback delivered via email on teacher candidates' implementation of a multiple stimulus without replacement (MSWO) preference assessment with an adult confederate. Six participants enrolled in a special education teacher preparation program were recruited to participate. After exposure to an introductory MSWO training video, participant fidelity of MSWO administration was measured. Following baseline, performance feedback was delivered via e-mail to each participant after the completion of each research session. Results indicate that performance feedback delivered via e-mail improved fidelity of implementation for all six participants. Implications and future directions are discussed. The online version contains supplementary material available at 10.1007/s10864-022-09496-z.


Single Versus Multiple-Radii Cruciate-Retaining Total Knee Arthroplasty: An In Vivo Mobile Fluoroscopy Study.
Previous fluoroscopic studies, using static C-arm systems, have shown nonnormal kinematic patterns in cruciate-retaining (CR) total knee arthroplasty (TKA). This study compares in vivo the kinematic differences in subjects implanted with single sagittal radius (SR) vs multiradii (MR) CR TKA for various activities using a novel mobile fluoroscopic system. Using mobile fluoroscopy and 3D to 2D registration, tibiofemoral kinematics were analyzed for 25 subjects with an SR, symmetrical condylar CR TKA and 25 subjects with an MR, asymmetric condylar CR TKA for three dynamic weight-bearing activities: (1) deep knee bend (DKB), (2) walking up a ramp, and (3) walking down a ramp. During DKB, from full extension to maximum knee flexion, the SR (-0.43 ± 3.43 mm) and MR (-1.00 ± 3.23 mm) groups experienced statistically similar anterior/posterior (AP) motion in the lateral condyle. The SR (3.51 ± 2.68 mm) group had significant anterior movement compared to the MR (-0.42 ± 2.20 mm) group in the medial condyle. This resulted in a significantly larger amount of normal axial rotation experienced by the SR (5.20 ± 3.93°) group compared to the MR (0.75 ± 5.12°) group. During ramp activities, the SR TKA consistently exhibited a significantly more posterior position of both condyles compared to the MR TKA. Although the SR TKA exhibited larger amounts of axial rotation compared to the MR TKA in DKB, neither design exhibited weight-bearing kinematics as previously reported for the normal knee. Additional research on the normal knee for ramp activities is required to understand the importance of condylar position during these activities.


Two mating-type genes MAT1-1-1 and MAT1-1-2 with significant functions in conidiation, stress response, sexual development, and pathogenicity of rice false smut fungus Villosiclava virens.
Rice false smut caused by Villosiclava virens is one of the destructive diseases on panicles of rice. Sexual development of V. virens, controlled by mating-type locus, plays an important role in the prevalence of rice false smut and genetic diversity of the pathogen. However, how the mating-type genes mediate sexual development of the V. virens remains largely unknown. In this study, we characterized the two mating-type genes, MAT1-1-1 and MAT1-1-2, in V. virens. MAT1-1-1 knockout mutant showed defects in hyphal growth, conidia morphogenesis, sexual development, and increase in the tolerance to salt and osmotic stress. Targeted deletion of MAT1-1-2 not only impaired the sclerotia formation and pathogenicity of V. virens, but also reduced the production of conidia. The MAT1-1-2 mutant showed increases in tolerance to salt and hydrogen peroxide stress, but decreases in tolerance to osmotic stress. Yeast two-hybrid assay showed that MAT1-1-1 interacted with MAT1-1-2, indicating that those proteins might form a complex to regulate sexual development. In addition, MAT1-1-1 localized in the nucleus, and MAT1-1-2 localized in the cytoplasm. Collectively, our results demonstrate that MAT1-1-1 and MAT1-1-2 play important roles in the conidiation, stress response, sexual development, and pathogenicity of V. virens, thus providing new insights into the function of mating-type gene.


Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors.
Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias' treatment. Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman's method. We calculated also physicochemical and structural parameters for CNS delivery. The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.


Proteomic identification of the candidate target proteins of 15-deoxy-delta12,14-prostaglandin J2.
15-Deoxy-delta12, 14-prostaglandin J(2) (15d-PGJ(2)) is an endogenous anti-inflammatory lipid derived from PGD(2). One potential mechanism for its activity is the covalent modification of cellular proteins, via a reactive α,β-unsaturated carbonyl group in its cyclopentenone ring, which in turn alters protein function. In order to identify the candidate target proteins covalently modified by 15d-PGJ(2) in human aortic endothelial cell (EC), EC was treated with biotinylated-15d-PGJ(2), the modified proteins extracted by Neutravidin affinity-purification and the proteins identified by LTQ Orbitrap mass spectrometer. Classification of the 358 identified proteins was performed using PANTHER classification system (www.pantherdb.org), showing that the proteins mapped to metabolic process, cellular process, and transport activity. This protein data set highlights the potential for 15d-PGJ(2) to covalently modify cellular proteins and provides a source of data that will aid further studies on the mechanism of action of this endogenous regulator of inflammation.


Protease-Activated Receptor Antagonist for Reducing Cardiovascular Events - A Review on Vorapaxar.
Acute Coronary Syndrome (ACS) is a term that describes pathologies related to myocardial ischemia, and is comprised of unstable angina, non-ST elevation myocardial infarction, and ST elevation myocardial infarction. Urgent management of ACS is typically necessary to prevent future morbidity and mortality. Current medical recommendations of ACS management involve use of dual antiplatelet therapy, typically with aspirin and clopidogrel. However, newer therapies are being designed and researched to improve outcomes for patients with ACS. Vorapaxar is a novel antiplatelet therapy that inhibits thrombin-mediated platelet aggregation to prevent recurrence of ischemic events. It has been Food and Drug Administration approved for reduction of thrombotic cardiovascular events in patients with a history of MI or peripheral arterial disease with concomitant use of clopidogrel and/or aspirin, based upon the findings of the TRA 2°P-TIMI 50 trial. However, Vorapaxar was also found to have a significantly increased risk of bleeding, which must be considered when administering this drug. Based upon further subgroup analysis of both the TRA 2°P-TIMI 50 trial and TRACER trial, Vorapaxar was found to be potentially beneficial in patients with peripheral artery disease, coronary artery bypass grafting, and ischemic stroke. There are current trials in progress that are further evaluating the use of Vorapaxar in those conditions, and future research and trials are necessary to fully determine the utility of this drug.


Estriol serum levels, neonatal vitality and stromal villous edema in diabetic pregnancies.
Estriol serum levels, neonatal vitality and stromal villous edema were studied in diabetic pregnancies. The average serum estriol levels in diabetic patients whose placentas had villous edema was 26.45 +/- 9.16 ng/ml. This value was significantly lower than that of the diabetic patients without villous edema (59.26 +/- 12.06 ng/ml). The average serum estriol levels in diabetic patients who gave birth to depressed newborns was 25.68 +/- 9.73 ng/ml. In diabetic women who gave birth to vigorous newborns this value was 56.57 +/- 14.10 ng/ml. The difference was statistically significant. These results and similar findings from other authors are discussed.


NTRK point mutations and their functional consequences.
The neurotrophic receptor tyrosine kinase (NTRK) family of genes, including NTRK1, NTRK2, and NTRK3, encodes membrane-bound receptors that normally regulate cell survival and differentiation upon binding of growth factors. Not surprisingly, mutations in these genes are known to contribute to the growth of a diverse number of cancers. With the recent FDA approval of two first-generation tyrosine-kinase inhibitors (TKIs) for adult and pediatric patients with solid tumors harboring NTRK gene fusions, much of the literature has focused on the biology behind these types of NTRK abnormalities; however, point mutations can also contribute to oncogenesis or resistance to TKI therapy, albeit at a lower frequency than fusions. This review focuses on NTRK gene mutations that are associated with resistance to directed therapies, mutations detected in the primary setting that confer increased oncogenic activity, and evidence that suggests that some of these variants may be treated using specific targeted therapies. Finally, this review focuses on the detection of point mutations, including the utility of cell-free DNA (cfDNA) for monitoring the acquisition of resistance mutations.


Is malarial anaemia homologous to neocytolysis after altitude acclimatisation?
Malaria patients frequently develop severe anaemia that can persist after Plasmodium infection has been cleared from the circulation. This puzzling phenomenon involves massive death of young uninfected erythrocytes at a time when parasitic infection is very low. We have observed striking similarities in erythrocyte homoeostasis during altitude acclimatisation and Plasmodium infection, both of which initially induce an increase in circulating erythropoietin (Epo). Decreasing levels of Epo after return to low altitudes induce the death of young erythrocytes, a phenomenon called neocytolysis. In a similar way, we propose that Epo, which peaks during acute malaria and decreases after parasite clearance, could be contributing to anaemia causing neocytolysis during recovery from Plasmodium infection.


Sterols and oxysterols in immune cell function.
Intermediates in the cholesterol-biosynthetic pathway and oxysterol derivatives of cholesterol regulate diverse cellular processes. Recent studies have expanded the appreciation of their roles in controlling the functions of cells of the innate and adaptive immune systems. Here we review recent literature reporting on the biological functions of sterol intermediates and oxysterols, acting through transcription factors such as the liver X receptors (LXRs), sterol regulatory element-binding proteins (SREBPs) and the G protein-coupled receptor EBI2, in regulating the differentiation and population expansion of cells of the innate and adaptive immune systems, their responses to inflammatory mediators, their effects on the phagocytic functions of macrophages and their effects on antiviral activities and the migration of immune cells. Such findings have raised many new questions about the production of endogenous bioactive sterols and oxysterols and their mechanisms of action in the immune system.


Incomplete Brown-Séquard syndrome caused by cervical kyphosis secondary to neurofibromatosis: report of a case.
The case of a 17-year-old boy who suffered from incomplete Brown-SEquard syndrome caused by dystrophic cervical kyphosis secondary to neurofibromatosis is presented. He became aware of weakness of his left upper and lower extremities and was unable to walk within 1 month of his first feeling numbness in the right upper and lower extremities. Thereafter his condition deteriorated rapidly. On radiological investigation the entire dural sac was shifted anteriorly and the spinal cord was flattened anteroposteriorly and asymmetrically at the angular kyphosis level, as in Hirayama's disease. Despite morphological similarities to Hirayama's disease, this patient presented with quite different clinical features: incomplete Brown-SEquard syndrome and rapidly progressive symptoms. It is suspected that the myelopathy in this case can be attributed to compression of the spinal cord between the vertebral body and the posterior dural wall on only one side. He was successfully treated with posterior interspinous wiring combined with anterior decompression and fusion. The neurological deficit fully disappeared, and complete bony union was obtained 1 year after the operation.


Mechanism of action of bovine testicular hyaluronidase. Mapping of the active site.
The reactions of purified, homogeneous bovine testicular hyaluronidase have been studied with radioactively labeled oligomers of hyalobiuronic acid, (GlcUA-GlcNAc)n, as substrates and acceptors. Transglycosylation occurs by transfer of a glycosyl residue with retention of configuration from a leaving group to an acceptor. On the basis of detailed examination of cleavage and transglycosylation patterns for the trimer; comparison of trimer, tetramer, and polymer as substrates; comparison of acceptors; equilibrium binding; and other data, it is proposed that the enzyme's active site consists of five subsites for hyalobiuronate residues. In the terminology of Schechter, I., and Berger, A. ((1966) Biochemistry 5, 3371), these are s2-s1-s' 2-s3, where the reducing terminus is to the right, and cleavage occurs between s1 and s' 1. It is proposed that subsite s'2 has a high affinity for a substrate residue, while s1 and s'1 have low substrate affinity, and s2 and s' 3 are intermediate in affinity. This proposal is seen to have mechanistic implications. The reactions of several substrates show similar bell-shaped pH dependences, with optima in the region of pH 5 to 5.5.


Physical-Chemical Characterization of Bilayer Membranes Derived from (±) α-Tocopherol-Based Gemini Lipids and Their Interaction with Phosphatidylcholine Bilayers and Lipoplex Formation with Plasmid DNA.
Membrane formation and aggregation properties of two series of (±) α-tocopherol-based cationic gemini lipids without and with hydroxyl functionalities at the headgroup region (TnS n = 3, 4, 5, 6, 8, and 12; THnS n = 4, 5, 6, 8, and 12) with varying polymethylene spacer lengths were investigated extensively while comparing with the corresponding properties of the monomeric counterparts (TM and THM). Liposomal suspensions of each cationic lipid were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), zeta potential measurements, and small-angle X-ray diffraction studies. The length of the spacer and the presence of hydroxyl functionalities at the headgroup region strongly contribute to the aggregation behavior of these gemini lipids in water. The interaction of each tocopherol lipid with a model phospholipid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC)-derived vesicles, was thoroughly examined by differential scanning calorimetry (DSC) and 1,6-diphenyl-1,3,5-hexatriene (DPH)-doped fluorescence anisotropy measurements. The binding efficiency of the cationic tocopherol liposomes with plasmid DNA (pDNA) was followed by an ethidium bromide (EB) exclusion assay and zeta potential measurements, whereas negatively charged micellar sodium dodecyl sulfate (SDS)-mediated release of the pDNA from various preformed pDNA-liposomal complexes (lipoplex) was studied by an ethidium bromide (EB) reintercalation assay. The structural transformation of pDNA upon complexation with liposome was characterized using circular dichroism (CD) spectroscopic measurements. Gemini lipid-pDNA interactions depend on both the presence of hydroxyl functionalities at the headgroups and the length of the spacer chain between the headgroups. Succinctly, we performed a detailed physical-chemical characterization of the membranes formed from cationic monomeric and gemini lipids bearing tocopherol as their hydrophobic backbone and describe the role of inserting the -OH group at the headgroup of such lipids.


Congenital Na+ diarrhea: a new type of secretory diarrhea.
We report a new type of congenital "secretory diarrhea" in a 9-year-old girl that led to contraction and severe metabolic acidosis in the first weeks of life. Her fecal Na+ concentration was high and the pH alkaline. All known causes of secretory diarrhea were excluded. Our findings indicate a defect in the handling of Na+ and H+ in the distal ileum and colon. Treatment with orally administered Na-K-citrate supplementation has normalized her fluid and electrolyte status and allowed normal growth and psychomotor development, but the diarrhea has persisted.


Qualitative and Quantitative Study on Components of Future Time Perspective and Their Association with Persistent Treatment for Type 2 Diabetes.
Future time perspective (FTP) means the capacity to foresee, anticipate, and plan for future desired outcomes, and it contributes to persistent treatment for type 2 diabetes mellitus (T2DM). However, the components of FTP specific to T2DM patients have not been clarified. This study aimed to explore the components of FTP and to examine the associations between such components and persistent/impersistent diabetes treatment. In this cross-sectional study, using qualitative and quantitative methods, 106 T2DM patients were enrolled by purposive sampling. The participants were interviewed in October and November 2018 by public health nurses in Koriyama City Public Health Center, Japan. In addition to the participants' status of treatment engagement (persistent/impersistent), their responses regarding reasons for persistent/impersistent treatment were collected and then summarized into nine subthemes, which were then merged into two main themes according to the presence or absence of FTP with a sense of T2DM ownership for analysis. The main theme, "presence of FTP with a sense of T2DM ownership," included subthemes such as "securing social independence," "planning on living a long and healthy life," "prioritizing avoiding being a burden on family and friends," "valuing improvement of diabetes," "avoiding tragic results," "optimistically viewing treatment as a form of self-development," and "improving mental health," whereas the main theme, "absence of FTP with a sense of T2DM ownership," included "lack of consciousness of disease" and "living a dissipated life." The association between the presence of FTP with a sense of T2DM ownership and persistent treatment for T2DM was found using Fisher's exact test (p < 0.001). Health care professionals should support T2DM patients in having an FTP with a sense of T2DM ownership and purpose in life instead of treatment goals when such patients mention their dissipated life or lack of insight into the disease.


Actifit® scaffold implantation: Influence of preoperative meniscal extrusion on morphological and clinical outcomes.
Meniscal substitutes have been suggested for the treatment of knee pain after partial meniscectomy. However, despite the partial nature of the initial meniscectomy, secondary extrusion of the substitute is common. The primary objective of this study was to evaluate morphological outcomes of meniscal substitute implantation and their potential associations with preoperative meniscal extrusion. Preoperative absolute meniscal extrusion in the coronal plane predicts poorer morphological and clinical outcomes. Consecutive patients who received an Actifit(®) meniscal substitute between 2008 and 2011 were included prospectively. After 1 year and 2 years, the IKDC score and KOOS were determined and magnetic resonance imaging performed. The morphological evaluation consisted in measuring meniscal extrusion and cartilage coverage by the substitute in the coronal and sagittal planes. Twenty patients were included. Among them, 3 required subsequent removal of the substitute. The mean subjective IKDC score increased from 48.1 preoperatively to 56.4 after 2 years. Over the same period, the function/sports/recreational activities component of the KOOS improved significantly (42.9 vs. 55.0, P=0.04). Positive correlations between preoperative and 1-year values were demonstrated for both cartilage coverage in the coronal and the sagittal planes (P=0.03 and P=0.04, respectively) and coronal absolute meniscal extrusion (P=0.05). No significant differences were found between preoperative and 2-year values of cartilage coverage in the coronal and sagittal planes (P=0.38). There was a negative correlation linking preoperative meniscal extrusion in the coronal plane to 1-year cartilage coverage in the coronal and sagittal planes (P=0.01 and P=0.04, respectively). Preoperative absolute meniscal extrusion in the coronal plane correlated negatively with the subjective IKDC score after 1 year (P=0.02). Preoperative meniscal extrusion in the coronal plane strongly predicts clinical and morphological outcomes. Marked preoperative meniscal extrusion, even in a patient with symptoms after partial meniscectomy, should prompt an appraisal of whether allograft replacement may be more appropriate than a meniscal substitute. IV, prospective study.


Inhibition of aldosterone formation by cortisol in rat adrenal mitochondria.
In this work we confirm by a metabolic method the existence of at least two enzymes with 11 beta- and 18-hydroxylase activities in rat adrenal mitochondria. The method was based on the ability of cortisol (F), a foreign alternative substrate, to inhibit competitively metabolite productions from various precursors. F inhibited a) aldosterone (ALDO) production from 11-deoxycorticosterone (DOC) without affecting the yields of corticosterone (B) and 18-hydroxy-11-deoxycorticosterone (18-OHDOC); b) 18-hydroxycorticosterone and aldosterone productions from B (Ki = 2.5 +/- 0.5 microM); and c) ALDO production from 18-OHDOC. These results suggest the existence of two categories of enzymes with both 11 beta- and 18-hydroxylase activities, one comprising those that catalyze the conversions of DOC to B and 18-OHDOC (F-insensitive reactions [FIS]) and the other one comprising the enzymes involved in the conversions of B to 18-OHB and ALDO and that of 18-OHDOC to ALDO (F-sensitive reactions [FS]). The cloned enzymes CYP11B1 and CYP11B2 would pertain respectively to the FIS and FS categories.


Functional analysis of SlNCED1 in pistil development and fruit set in tomato (Solanum lycopersicum L.).
Abscisic acid (ABA) is an important regulator of many plant developmental processes, although its regulation in the pistil during anthesis is unclear. We investigated the role of 9-cis-epoxycarotenoid dioxygenase (SlNCED1), a key ABA biosynthesis enzyme, through overexpression and transcriptome analysis in the tomato pistil. During pistil development, ABA accumulates and SlNCED1 expression increases continually, peaking one day before full bloom, when the maximum amount of ethylene is released in the pistil. ABA accumulation and SlNCED1 expression in the ovary remained high for three days before and after full bloom, but then both declined rapidly four days after full bloom following senescence and petal abscission and expansion of the young fruits. Overexpression of SlNCED1 significantly increased ABA levels and also up-regulated SlPP2C5 expression, which reduced ABA signaling activity. Overexpression of SlNCED1 caused up-regulation of pistil-specific Zinc finger transcription factor genes SlC3H29, SlC3H66, and SlC3HC4, which may have affected the expression of SlNCED1-mediated pistil development-related genes, causing major changes in ovary development. Increased ABA levels are due to SlNCED1 overexpresson which caused a hormonal imbalance resulting in the growth of parthenocarpic fruit. Our results indicate that SlNCED1 plays a crucial role in the regulation of ovary/pistil development and fruit set.


The correlation between lateralization of intracerebral hemorrhage in basal ganglia and handedness.
To investigate the correlation between lateralization of cerebral basal ganglia hemorrhage and handedness. Medical records and computed tomography (CT) scans for 84 patients with primary hypertensive intracerebral hemorrhage (ICH) in basal ganglia were reviewed. Data of gender, age, handedness, and location of basal ganglia hematoma were statistically analyzed. Data of age, gender, handedness, health condition, and mean blood flow velocity (BFV) in middle cerebral arteries (MCAs) and anterior cerebral arteries (ACAs) on both sides of 114 healthy individuals were statistically analyzed. We found out that the patients with right basal ganglia hemorrhage were mostly left-handed, while patients with left basal ganglia hemorrhage were mostly right handed (p=0.021, r=0.251). And the mean BFV in the right MCAs of left-handed ones are relatively higher, the mean BFV in the left MCAs of right-handers are relatively higher (p=0.008, r=0.248). There 's a correlation between lateralization of cerebral basal ganglia hemorrhage and handedness.


Photosynthetic response to sunflecks in the desiccation-tolerant fern Polypodium virginianum.
The photosynthetic response to sunflecks was investigated in the fern Polypodium virginianum growing on cliff edges of the Niagara Escarpment, in southern Ontario, Canada. Ferns were exposed to natural precipitation, continuous watering, or continuous drought prior to exposure to artificial sunflecks. The results were analyzed using temperature, humidity and previous exposure to light as covariates. The response to sunflecks was extremely rapid and showed no measurable induction period in the field. Controlled experiments completed in the laboratory showed exceptionally short induction periods. Previous exposure to sunflecks, and desiccation did not influence the time constants of response to sunflecks although drying did reduce maximum rates of CO2 exchange. Polypodium virginianum shows an extremely rapid response to fluctuations in the supply of light, and this is interpreted to be advantageous to this species because of the array of extremely hostile conditions that occur at cliff edges.


A striatal serotonergic involvement in the behavioural effects of anticholinesterase organophosphates.
Acute administration of the anticholinesterase agents diisopropylfluorophosphate, soman, sarin and tabun to rats in sub-convulsive doses produced tremors and hind-limb abduction. The ratios of the levels of 5-HIAA to 5-HT in the striatum showed a consistent tendency to be increased, suggesting an increase in 5-HT turnover. Both the behavioural and the biochemical changes were antagonized by atropine. The possible involvement of a cholinergic-serotonergic interaction in these tremors and hind-limb abduction is discussed.


Postoperative lactate concentrations predict the outcome of infants aged 6 weeks or less after intracardiac surgery: a cohort follow-up to 18 months.
An observational cohort study was conducted in infants less than 6 weeks of age undergoing intracardiac surgery to examine the predictive value of serial postoperative lactate determination on survival and early childhood neurodevelopment. A total of 85 infants with congenital heart disease underwent intracardiac surgery between 1996 and 1999. Differences in serial lactate concentrations after surgery among 3 outcome groups were compared. The predictive value of plasma lactate concentration on outcome (1) at discharge from initial hospitalization and (2) 18 to 24 months postnatal age was examined. Compared with survivors, the nonsurvivors had higher lactate concentrations on admission to the pediatric intensive care unit at day 1 peak and area under the curve of the lactate profile than those of adverse and intact survivors (all P < .001, analysis of variance). Significant differences in the time for lactate concentrations to return to 2 mmol/L or less during the first postoperative day were observed among the groups: nonsurvivors > adverse survivors > intact survivors. Lactate concentrations of less than 7 mmol/L on admission or less than 8 mmol/L at day 1 peak predicted survival with 82% sensitivity and 83% specificity, and positive and negative predictive values of 97% and 43%, respectively (P < .001, chi2). Plasma lactate concentrations were associated with adverse outcome but had lower predictive values compared with that for nonsurvival. Serial lactate determination accurately predicts survival and may help differentiate survivors with adverse outcome from those with intact neurodevelopment in early childhood.


Size, shape, charge and "stealthy" surface: Carrier properties affect the drug circulation time in vivo.
The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time. For most drugs, sufficient in vivo circulation time is the basis of high bioavailability. Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system, to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect. The physical and chemical properties of drug carriers, such as size, shape, surface charge and surface modification, would affect their in vivo circulation time, metabolic behavior and biodistribution. The final circulation time of carriers is determined by the balance between macrophage recognitions, blood vessel penetration and urine excretion. Therefore, when designing the drug delivery system, we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually. This article mainly reviews the effect of carrier size, size, surface charge and surface properties on its circulation time in vivo, and discusses the mechanism of these properties affecting circulation time. This review has reference significance for the research of long-circulation drug delivery system.


Crystal structure of fac-tricarbon-yl(quinoline-2-carboxyl-ato-κ(2) N,O)(tri-phenyl-arsane-κAs)rhenium(I).
In the title compound, [Re(C10H6NO2)(CO)3{As(C6H5)3}], the coordination environment of Re(I) is that of a distorted octa-hedron. Three coordination sites are occupied by three carbonyl groups in a facial arrangement and the remaining three sites by tri-phenyl-arsane and deprotonated quinaldic acid in As-mono- and N,O-bidentate fashions, respectively. In the crystal, the complexes are linked through weak C-H⋯O hydrogen bonds, forming a three-dimensional network. It worth noting that, as far as we know, this complex is the first Re(I) tri-phenyl-arsane tricarbonyl compound to be reported.


High resolution melting analysis as a tool to detect molecular markers of antiviral resistance in influenza A viruses.
A real-time PCR followed by high resolution melting analysis (HRMA) was developed, for rapid detection of antiviral resistance markers in influenza A viruses, of both H1N1 and H3N2 subtypes. The targets of these assays were the nucleotide substitution G806A (S31N mutation) in the M gene as marker of resistance to adamatanes in influenza viruses A(H3N2), the substitution A356T (E119V mutation) in the N2 gene of influenza viruses A(H3N2) and the substitution C823T (H274Y mutation) in the N1 gene of the pandemic A(H1N1) 2009 virus as markers of oseltamivir resistance. First, the designed primers and the overall protocol of the HRMA were validated using already characterized viral isolates either containing or lacking changes at the tested codons. Then, HRMA was used to search for the marker of oseltamivir resistance in 75 clinical samples, H1N1 2009 positives, analyzed previously by pyrosequencing and Sanger sequencing, and of both adamantane-derivatives and oseltamivir resistance in 57 H3N2 positive clinical samples. The results of HRMA of the H1N1 2009 isolates were in agreement with those obtained by sequencing. As regards the H3N2 isolates, HRMA revealed a widespread resistance to adamantanes with 89.5% nucleotide substitution G806A, while 3% were resistant to oseltamivir (A356T change). HRMA, applied to the detection of markers of resistance to antiviral drugs against influenza A viruses, confirmed to be a procedure flexible, low cost and time-saving, suitable for application to epidemiological surveys and in clinical settings for diagnostic purposes.


Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL.
Patients harboring CRLF2-rearranged B-lineage acute lymphocytic leukemia (B-ALL) face a 5-year survival rate as low as 20%. While significant gains have been made to position targeted therapies for B-ALL treatment, continued efforts are needed to develop therapeutic options with improved duration of response. Here, first we have demonstrated that patients with CRLF2-rearranged Ph-like ALL harbor elevated thymic stromal lymphopoietin receptor (TSLPR) expression, which is comparable with CD19. Then we present and evaluate the anti-tumor characteristics of 1B7/CD3, a novel CD3-redirecting bispecific antibody (BsAb) that co-targets TSLPR. In vitro, 1B7/CD3 exhibits optimal binding to both human and cynomolgus CD3 and TSLPR. Further, 1B7/CD3 was shown to induce potent T cell activation and tumor lytic activity in both cell lines and primary B-ALL patient samples. Using humanized cell- or patient-derived xenograft models, 1B7/CD3 treatment was shown to trigger dose-dependent tumor remission or growth inhibition across donors as well as induce T cell activation and expansion. Pharmacokinetic studies in murine models revealed 1B7/CD3 to exhibit a prolonged half-life. Finally, toxicology studies using cynomolgus monkeys found that the maximum tolerated dose of 1B7/CD3 was ≤1 mg/kg. Overall, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 in patients with CRLF2-rearranged B-ALL.


Lactate dehydrogenase kinetics predict chemotherapy response in recurrent metastatic nasopharyngeal carcinoma.
Lactate dehydrogenase (LDH) is a known prognostic biomarker for the endemic variant of nasopharyngeal carcinoma (NPC). Here, we investigate whether serial changes in LDH level between chemotherapy (CT) cycles are associated with tumour response to CT. Patients with biopsy-proven, recurrent or treatment-naïve metastatic NPC (mNPC) were recruited. All patients had received at least two cycles of platinum-based doublet or triplet CT, with serial assessment of LDH prior to every cycle of chemotherapy (CT1-6). Patients harbouring conditions that affect LDH levels (IU/L) were excluded. Tumour response was assessed after every two cycles of CT by RECIST v1.1. A total of 158 patients were analysed, including 77 with recurrent and 81 with treatment-naïve mNPC. High pre-CT LDH was associated with an inferior overall survival [hazard ratio 1.93 for ⩾240 versus <240 (1.34-2.77), p < 0.001], which is consistent with published literature. We found that both absolute LDH levels and LDH ratios (LDHCTn: LDHCTn-1) were associated with tumour response [partial response versus progressive disease: median value across CT1-6 = 168-190 versus 222-398 (absolute); 0.738-0.988 versus 1.039-1.406 (ratio)], albeit LDH ratio had a tighter variance between patients. Finally, we showed that an LDH ratio cut-off of 1.0 at CT1, CT3 and CT5 was predictive of progressive disease at CT2, CT4, CT6 [area under the curve of 0.73 (0.65-0.80)]. Herein, we characterised the longitudinal variation of LDH in response to CT in mNPC. Our findings suggest the potential utility of interval LDH ratio to predict subsequent tumour response to CT.