Drug combination approach to overcome resistance to EGFR tyrosine kinase inhibitors in lung cancer.
The discovery of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) has led to unprecedented clinical response in a subset of lung cancer patients carrying the sensitizing EGFR mutations (L858R or exon 19 deletion). However, disease progression invariably occurs within a year after the initial TKI treatment, predominantly due to the development of acquired resistance caused by the secondary EGFR T790 M mutation. Numerous second generation irreversible and third generation EGFR T790 M selective EGFR TKIs have been developed to overcome resistance. Besides developing new EGFR TKIs, combination therapy represents another promising strategy to combat resistance. This approach aims at circumventing drug resistance through a so-called bypass signaling mechanism by targeting horizontal pathways or vertical pathways or both. The logical combinations of different molecular targeted drugs inhibiting various oncogenic signaling have been studied. On the other hand, the repurposing of drugs with indications other than oncology has also emerged as a promising approach. In this review, we focus on the effectiveness of combination therapy of EGFR-TKIs with different agents in advanced lung cancer.


Increased apoptosis in remote non-infarcted myocardium in multivessel coronary disease.
Multivessel coronary disease after myocardial infarction is a major risk factor for unfavorable cardiac remodeling and death due to pump failure, but underlying pathophysiologic mechanisms are still uncompletely established. Post-infarction myocardial apoptosis has been recently implicated as a cause of ongoing cell loss leading to cardiac failure. Our aim was to assess the role of post-infarction myocardial apoptosis and pro-apoptotic factor expression in the non-infarcted remote myocardium of subjects with multivessel coronary disease. Twenty-one males dying after recent myocardial infarction with permanent occlusion of the infarct-related artery were selected at autopsy. Apoptosis was assessed at viable myocardial regions remote from infarction by co-staining for in situ end-labeling of DNA fragmentation and cleaved caspase-3. Expression of pro-apoptotic factor bax and hypoxia-induced factor-1alpha was evaluated by immunohistochemistry. Subjects with multivessel disease (N=11) showed a significantly two-fold higher myocardial apoptosis in comparison to subjects with single vessel disease (N=10) (0.9% vs. 0.5%, p=0.013). Similarly, myocardial bax expression was increased in patients with multivessel disease (3.0% vs. 1.4%, p=0.029). Stratification for the number of diseased coronary vessels confirmed the association between extent of coronary disease and apoptotic rates (p=0.022). Even in subjects dying over 30 days after infarction multivessel disease remained predictive of enhanced myocardiocyte apoptosis at remote regions (p=0.033). Post-infarction myocardial apoptosis and bax expression in remote left ventricular regions are significantly increased in male patients with multivessel coronary disease in comparison to those with isolated infarct-related artery occlusion. These findings suggest that apoptotic cell loss in the viable non-infarcted myocardium, possibly due ongoing ischemia, may play a relevant role in the unfavorable clinical course typical of multivessel disease after myocardial infarction.


[Interlaboratory variation in the prenatal screening test for neural tube closing defects].
Early detection of neural-tude defects is possible by determining Alpha-fetoprotein (AFP) in maternal serum. 16'685 pregnant women were observed. Three methods for the determination of the "normal" range are compared. The first one, already used in similar studies, makes use of a constant multiple of the median. The other two ones make use of robust estimates of location and scale. Their comparison shows the interest of the robust methods to reduce the interlaboratory variability.


Diagnostic Yield of Body CT and Whole-Body FDG PET/CT for Initial Systemic Staging in Patients With Suspected Primary CNS Lymphoma: A Systematic Review and Meta-Analysis.
BACKGROUND. Several guidelines recommend body imaging for the initial work-up of patients with suspected primary CNS lymphoma, to exclude subclinical systemic involvement. However, to our knowledge, the diagnostic yield of body CT (contrast-enhanced CT of the chest, abdomen, and pelvis) and whole-body FDG PET/CT for the evaluation of subclinical systemic lymphoma has not yet been systematically evaluated. OBJECTIVE. The purpose of this study was to investigate and compare the diagnostic yield of body CT and whole-body FDG PET/CT in detecting subclinical systemic lymphoma in patients with suspected primary CNS lymphoma. EVIDENCE ACQUISITION. A systematic search of the MEDLINE and EMBASE databases through July 5, 2020, was conducted to identify studies evaluating the diagnostic yield of body CT or whole-body FDG PET/CT in detecting subclinical systemic lymphoma in patients with suspected primary CNS lymphoma. Pooled estimates of the diagnostic yield of both imaging modalities were calculated using the DerSimonian and Laird random-effects model. The false referral rate and the rate of incidental secondary malignancy were also pooled. EVIDENCE SYNTHESIS. Nine original articles on studies evaluating a total of 1040 patients were included. In detecting subclinical systemic lymphoma, the pooled diagnostic yields of body CT and whole-body FDG PET/CT were 2.5% (95% CI, 1.5-3.9%) and 4.9% (95% CI, 2.8-8.5%), respectively. In the subgroup analysis, the diagnostic yield of whole-body FDG PET/CT was significantly higher than that of body CT (p = .03). Four studies reported changes in the management plan: the R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) regimen with or without radiation therapy was added if extracranial lymphoma involvement was detected by body CT or whole-body FDG PET/CT. The pooled false referral rate of whole-body FDG PET/CT was 5.3% (95% CI, 2.2-12.0%). The pooled rate of incidental secondary malignancy detected on whole-body FDG PET/CT was 3.1% (95% CI, 1.7-5.6%). CONCLUSION. Body imaging should be used in the initial workup of patients with suspected primary CNS lymphoma, to exclude systemic involvement. Whole-body FDG PET/CT may be a better alternative to body CT. CLINICAL IMPACT. Our results support current National Comprehensive Cancer Network guidelines for the use of body imaging to exclude subclinical systemic involvement in patients with suspected primary CNS lymphoma.


The effect of ultraviolet and white light on growth rate, lysis, and phage production of Bacillus megatherium.
Cultures of megatherium 899a, growing under different conditions, were exposed to ultraviolet or white light. 1. Cultures exposed to ultraviolet light and then to white light continue to grow at the normal rate. Cultures exposed to ultraviolet light and then placed in the dark grow at the normal rate for varying lengths of time, depending on conditions, and then lyse with the liberation of from 5 to 1000 phage particles per cell, depending on the culture medium. 2. Increasing the time of exposure to ultraviolet light results in an increase in the fraction of cells which lyse in the dark. The lysis time decreases at first, remains constant over a wide range of exposure, and then increases. The lysis can be prevented by visible light after short exposure, but not after long exposures. 3. The time required for lysis is independent of the cell concentration. 4. Effect of temperature. After exposure to ultraviolet the cell concentration increases about 4 times at 20 degrees , 30 degrees , or 35 degrees C., but only 1.5 to 2.0 times at 40-45 degrees . This is due to the fact that the growth rate of the culture reaches a maximum at 38 degrees while the lysis rate increases steadily up to 45 degrees . 5. Terramycin decreases the growth rate and lysis rate in proportion. 6. At pH 5.1, the cultures continue to grow slowly in the dark after exposure to ultraviolet light. 7. Megatherium sensitive cells infected with T phage lyse more rapidly than ultraviolet-treated 899a, and visible light does not affect the lysis time. The results agree with the assumption that exposure to ultraviolet results in the production of a toxic (mutagenic) substance inside the bacterial cell. This substance is inactivated by white light.


Synthesis, Crystal and Electronic Structures of a Thiophosphinoyl- and Amino-Substituted Metallated Ylide.
Invited for this month's cover is the group of Viktoria H. Gessner at the Ruhr-University in Bochum (Germany). The cover shows the structure of the newly reported, isolated metallated ylide. Due to the high negative charge at the ylidic carbon center this compound is "on fire", but can be stabilized by smart molecular design. Structure analyses of the different alkali metal complexes combined with computational studies provide insights into the electronic structure of the compounds Read the full text of their Communication at 10.1002/open.202100178.


Anti-anxiety effects of progesterone and some of its reduced metabolites: an evaluation using the burying behavior test.
In this study, pregnenolone sulfate, progesterone and some of its main reduced metabolites were tested for anxiolytic properties in rats using the burying behavior paradigm. All steroids were subcutaneously injected. Progesterone (0.5, 1.0, 2.0 and 4.0 mg/rat) and its 3 alpha-5 alpha-reduced metabolite (0.125, 0.250, 0.5 and 1.0 mg/rat) produced a clear dose-dependent anxiolytic response, without affecting the spontaneous ambulatory behavior. 5 alpha-Pregnanedione decreased burying behavior only at the highest dose (4.0 mg/rat). Pregnenolone sulfate (1.0, 2.0 and 4.0 mg/rat), 5 beta-pregnanedione and 3 beta- or 5 beta-pregnenolones were devoid of effects. The 3 beta-5 beta-reduced metabolite of progesterone (2.0 and 4.0 mg/rat) decreased motor activity, without altering the burying behavior. These results demonstrate that the 3 alpha-5 alpha metabolite of progesterone shows the highest anxiolytic potency in the burying behavior test, when compared with all steroids evaluated. The data are discussed in terms of the close structure-activity relationship requirements of steroids to stimulate the GABA/benzodiazepine receptor-chloride ionophore complex.


Copper and zinc in four freshwater fish species from Lake Pamvotis (Greece).
Lake ecosystems are vulnerable to heavy-metal pollution. Fish samples are considered as one of the most indicative factors, in freshwater systems, for the estimation of trace metals pollution potential. Lake Pamvotis (NW Greece) is a typical Mediterranean ecosystem of great importance in regard to biodiversity and to aesthetic value. The fish species found most commonly in the lake are Cyprinus carpio, Silurus aristotelis, Rutilus ylikiensis, and Carassius gibelio. The aim of the present study is to evaluate the level of contamination of two essential heavy metals (copper and zinc) appearing at high concentrations in lake water in the above four fish species. Metal concentrations were measured by atomic absorption spectroscopy in three different tissues (muscle, liver, gonads) in order to assess the fish contamination. A two-factor analysis of variance, based on the procedure of general linear models, was employed in which fish species (four levels) and fish tissue (three levels) were examined for potential influence on Cu and Zn concentrations. Differences between level means per factor were treated using Tukey's multiple comparisons of means. The study showed that C. carpio and R. ylikiensis presented the highest metal content. Tissues analysis revealed that liver and gonads accumulated the highest levels of Cu and Zn. Metal concentration in the edible part of the examined fish (muscle) were in the safety-permissible levels for human consumption.


Secondary involvement of the central nervous system in malignant non-Hodgkin's lymphoma. A study of 30 cases in a series of 498 patients.
Of 498 patients with non-Hodgkin's lymphoma (NHL), 30 showed secondary central nervous system (CNS) involvement. Of these 30 patients, 26 had high-grade malignancy and 21 lymphoblastic lymphoma, mainly convoluted (n = 8) or Burkitt (n = 6) type according to the Kiel classification. In half of the 30 patients, CNS involvement was associated with progressive lymphoma. Bone marrow involvement was found in half of the patients before or at the time of the diagnosis of CNS involvement, which was 12 months (mean) after the diagnosis of NHL. Eight patients received CNS prophylaxis. Results of treatment for CNS involvement are poor (mean survival time from CNS involvement: 3.5 months). The Kiel classification allows good identification of patients at high risk of CNS lymphoma: systematic CNS prophylaxis is indicated only in the convoluted and Burkitt types. An efficient prophylaxis must be found and results must be confirmed by other studies.


Increased risk of A(H1N1)pdm09 influenza infection in UK pig industry workers compared to a general population cohort.
Pigs are mixing vessels for influenza viral reassortment, but the extent of influenza transmission between swine and humans is not well understood. To assess whether occupational exposure to pigs is a risk factor for human infection with human and swine-adapted influenza viruses. UK pig industry workers were frequency-matched on age, region, sampling month, and gender with a community-based comparison group from the Flu Watch study. HI assays quantified antibodies for swine and human A(H1) and A(H3) influenza viruses (titres ≥ 40 considered seropositive and indicative of infection). Virus-specific associations between seropositivity and occupational pig exposure were examined using multivariable regression models adjusted for vaccination. Pigs on the same farms were also tested for seropositivity. Forty-two percent of pigs were seropositive to A(H1N1)pdm09. Pig industry workers showed evidence of increased odds of A(H1N1)pdm09 seropositivity compared to the comparison group, albeit with wide confidence intervals (CIs), adjusted odds ratio after accounting for possible cross-reactivity with other swine A(H1) viruses (aOR) 25·3, 95% CI (1·4-536·3), P = 0·028. The results indicate that A(H1N1)pdm09 virus was common in UK pigs during the pandemic and subsequent period of human A(H1N1)pdm09 circulation, and occupational exposure to pigs was a risk factor for human infection. Influenza immunisation of pig industry workers may reduce transmission and the potential for virus reassortment.


Towards an optimal and unbiased approach for tumor cell isolation.
Our current understanding of clinical significance or the lack thereof of circulating tumor cells (CTCs) is biased by the technology used to isolate these rare cells. Despite the presence of a vast number of academic and commercial technologies, the lack of a standardized and optimized platform has been widely noted. We present a negative enrichment approach, integrating WBC depletion and chemical-free RBC depletion in the same setup without the need for centrifugation, washing or multiple sample handling steps. This approach achieves an average of >90 % recovery of spiked tumor cells and >99 % total WBC depletion in whole blood across multiple cell lines, in a simple and easy-to-use assay. The results presented herein and ongoing improvements aim to fulfill the need for a highly reliable, unbiased, standardized, and optimized CTC isolation platform, using component technologies that are validated for cell isolation.


Rapid method for diagnosis of abnormal activity of butyrylcholinesterase.
We present the results of spectral studies of the interactions between butyrylcholinesterase and ethidium bromide fluorophore inhibitor. The ethidium bromide fluorescence selectively increased in the presence of butyrylcholinesterase. A rapid method for evaluation of serum butyrylcholinesterase activity is developed.


A Large-Scale Exome-Wide Association Study Identifies Novel Germline Mutations in Lung Cancer.
Rationale: Genome-wide association studies have identified common variants of lung cancer. However, the contribution of rare exome-wide variants, especially protein-coding variants, to cancers remains largely unexplored. Objectives: To evaluate the role of human exomes in genetic predisposition to lung cancer. Methods: We performed exome-wide association studies to detect the association of exomes with lung cancer in 30,312 patients and 652,902 control subjects. A scalable and accurate implementation of a generalized mixed model was used to detect the association signals for loss-of-function, missense, and synonymous variants and gene-level sets. Furthermore, we performed association and Bayesian colocalization analyses to evaluate their relationships with intermediate exposures. Measurements and Main Results: We systematically analyzed 216,739 single-nucleotide variants in the human exome. The loss-of-function variants exhibited the most notable effects on lung cancer risk. We identified four novel variants, including two missense variants (rs202197044TET3 [Pmeta (P values of meta-analysis) = 3.60 × 10-8] and rs202187871POT1 [Pmeta = 2.21 × 10-8]) and two synonymous variants (rs7447927TMEM173 [Pmeta = 1.32 × 10-9] and rs140624366ATRN [Pmeta = 2.97 × 10-9]). rs202197044TET3 was significantly associated with emphysema (odds ratio, 3.55; Pfdr = 0.015), whereas rs7447927POT1 was strongly associated with telomere length (β = 1.08; Pfdr (FDR corrected P value) = 3.76 × 10-53). Functional evidence of expression of quantitative trait loci, splicing quantitative trait loci, and isoform expression was found for the four novel genes. Gene-level association tests identified several novel genes, including POT1 (protection of telomeres 1), RTEL1, BSG, and ZNF232. Conclusions: Our findings provide insights into the genetic architecture of human exomes and their role in lung cancer predisposition.


The effects of acute and chronic morphine treatment on the process of facial nerve regeneration.
Prominent cellular responses to axonal interruption include enhanced synthesis of RNA and protein in the neuronal perikaryon, and proliferation of reactive Schwann cells. Since morphine has been shown to significantly depress cellular metabolism, we examined its effect on these and other reparative responses underlying nerve fiber regeneration. Rat facial nerve trunks from saline, acute morphine, and continuous morphine-treated animals were examined by light and electron microscopy at 3, 7 and 14 days after crush injury. The number of axonal sprouts/unit area and the diameters of regenerating axons were quantified at each survival interval. Both saline-treated and acute morphine-treated facial nerves demonstrated myelin degradation and Schwann cell hypertrophy (at 3 days post-axotomy), sprout outgrowth (at 7 days) and axon maturation and myelination (at 14 days). In the chronic morphine-treated animals, a retardation of the regenerative process was evident. Axon sprout outgrowth and axonal diameters were reduced at 3 and 7 days post-axotomy. In treated 14-day animals, axon diameters were normal; however, significantly fewer axon profiles/unit area were observed. After chronic morphine exposure, Schwann cell hypertrophy and proliferation, as well as myelin debris removal, were inhibited at all survival periods.


Does coping mediate the relationship between familism and caregiver outcomes?
The sociocultural model of stress and coping, which despite receiving support from several studies conducted with diverse ethnic groups, has yet to be tested longitudinally or used within the context of positive caregiver outcomes. The aim of the current study was to test a specific component of the model, which posits that caregiver coping will be influenced by the cultural value of familism (feelings of solidarity and loyalty among family members), which will in turn affect caregiver outcomes. A questionnaire was completed by 123 family caregivers in the UK assessing familism, use of coping strategies, caregiver gains, anxiety and depression at three time points over nine months. Mediation analysis followed guidelines proposed by Baron and Kenny. Religious coping and positive reframing at time 2 (T2) were found to significantly mediate between familism values at time 1 (T1) and caregiver gains at time 3 (T3). Behavioural disengagement at T2 was found to mediate between familism at T1 and caregiver depression at T3. Additionally familism was found to be positively associated with both negative and positive aspects of caregiving. Our longitudinal findings suggest that interventions and services acknowledging caregiver values and the associated coping responses may prove beneficial.


Disheveled3 enhanced EMT and cancer stem-like cells properties via Wnt/β-catenin/c-Myc/SOX2 pathway in colorectal cancer.
Epithelial-to-mesenchymal transition (EMT) and cancer stem-like cells (CSLCs) play crucial role in tumor metastasis and drug-resistance. Disheveled3 (DVL3) is involved in malignant behaviors of cancer. However, the role and potential mechanism of DVL3 remain elusive in EMT and CSLCs of colorectal cancer (CRC). UALCAN and PrognoScan databases were employed to evaluate DVL3 expression in CRC tissues and its correlation with CRC prognosis, respectively. Transwell, sphere formation and CCK8 assay were used to assess metastasis, stemness and drug sensitivity of CRC cells, respectively. Western blotting and dual luciferase assay were performed to analyze the protein expression and Wnt/β-catenin activation, respectively. Lentiviral transfection was used to construct the stable cell lines. Animal studies were performed to analyze the effect of silencing DVL3 on tumorigenicity and metastasis of CRC cells in vivo. DVL3 was overexpressed in CRC tissues and several CRC cell lines. DVL3 expression was also higher in CRC tissues with lymph node metastasis than tumor tissues without metastasis, and correlated with poor prognosis of CRC patients. DVL3 positively regulated the abilities of migration, invasion and EMT-like molecular changes in CRC cells. Moreover, DVL3 promoted CSLCs properties and multidrug resistance. We further identified that Wnt/β-catenin was crucial for DVL3-mediated EMT, stemness and SOX2 expression, while silencing SOX2 inhibited DVL3-mediated EMT and stemness. Furthermore, c-Myc, a direct target gene of Wnt/β-catenin, was required for SOX2 expression and strengthened EMT and stemness via SOX2 in CRC cells. Finally, knockdown of DVL3 suppressed tumorigenicity and lung metastasis of CRC cells in nude mice. DVL3 promoted EMT and CSLCs properties of CRC via Wnt/β-catenin/c-Myc/SOX2 axis, providing a new strategy for successful CRC treatment.


Detection of left ventricular ischemia during atrial pacing: simultaneous assessment by echocardiography and invasive hemodynamic measurements.
The ability of cross-sectional echocardiography to detect myocardial ischemia induced by atrial pacing was assessed during cardiac catheterization in 11 patients with coronary arterial disease. Angina pectoris was precipitated in all patients with increase in left ventricular end-diastolic pressure after pacing by 5 +/- 6 (mean +/- standard deviation) mm Hg (P less than 0.01). Regional left ventricular dysfunction occurred during pacing in all patients as determined by quantitative echocardiographic assessment of wall motion. Simultaneously, systolic reduction in parasternal short-axis area decreased (from 42 +/- 13 to 28 +/- 9%, P less than 0.01) with concomitant decrease in ejection fraction as determined in the apical four-chamber view (from 49 +/- 5 to 40 +/- 8%, P less than 0.01). In conclusion, echocardiography may detect pacing-induced myocardial ischemia through detection of regional and global left ventricular dysfunction. Inadequate regional perfusion may be indicated by echocardiography even in patients without apparent evidence of ischemia as determined by invasive hemodynamic measurements.


[Focal atrial tachycardias: diagnostics and therapy].
In this article, typical characteristics of focal atrial tachycardias are described and a systematic approach regarding diagnostics and treatment options in the field of invasive cardiac electrophysiology (EP) is presented. Subjects of this article include the definition of focal atrial tachycardias, knowledge about localizing the origin of such, and guidance on how to approach an invasive EP study (e.g., administration of medication during the EP study to provoke tachycardias). Further, descriptions will be found on how to localize the origin of focal atrial tachycardias with the help of the 12-lead ECG and invasive three-dimensional mapping to successfully treat focal atrial tachycardias with catheter ablation.


Genome-Wide Prediction and Validation of Intergenic Enhancers in Arabidopsis Using Open Chromatin Signatures.
Enhancers are important regulators of gene expression in eukaryotes. Enhancers function independently of their distance and orientation to the promoters of target genes. Thus, enhancers have been difficult to identify. Only a few enhancers, especially distant intergenic enhancers, have been identified in plants. We developed an enhancer prediction system based exclusively on the DNase I hypersensitive sites (DHSs) in the Arabidopsis thaliana genome. A set of 10,044 DHSs located in intergenic regions, which are away from any gene promoters, were predicted to be putative enhancers. We examined the functions of 14 predicted enhancers using the β-glucuronidase gene reporter. Ten of the 14 (71%) candidates were validated by the reporter assay. We also designed 10 constructs using intergenic sequences that are not associated with DHSs, and none of these constructs showed enhancer activities in reporter assays. In addition, the tissue specificity of the putative enhancers can be precisely predicted based on DNase I hypersensitivity data sets developed from different plant tissues. These results suggest that the open chromatin signature-based enhancer prediction system developed in Arabidopsis may serve as a universal system for enhancer identification in plants.


A molecular marker for fibrotic collagen in lungs of infants with respiratory distress syndrome.
Lung samples from four infants who died of respiratory complications of prematurity (Infant Respiratory Distress Syndrome, IRDS) were analyzed for their content of various collagen crosslink amino acids by newly developed techniques of high-performance liquid chromatography. Comparable analyses were performed with tissue from stillborn infants with apparently normal lungs (control group) and from adults without apparent lung disease. We observed increased amounts of the difunctional crosslink dihydroxylysinonorleucine (DHLNL) in the IRDS lungs. Gestational age seemed to be the most important determinant of total lung content of the trifunctional crosslink hydroxypyridinium (OHP). Term infants had about one-third of the OHP content in their lung collagen as was found in the adult lungs. These observations suggest that there are important changes in the molecular structure of collagen in human fibrotic lung disease, changes that are paralleled in various animal models of experimental pulmonary fibrosis, and in various human diseases involving abnormalities of skin or bone collagen metabolism.


A novel splicing variant of VCAN identified in a Chinese family initially diagnosed with familial exudative vitreoretinopathy.
Wagner vitreoretinopathy (WVR) is a rare autosomal dominant vitreoretinopathy caused by pathogenic variants in the VCAN gene. The aim of this study was to report a novel splicing variant in VCAN identified in a three-generation Chinese family initially diagnosed with familial exudative vitreoretinopathy and to describe the patients' clinical features. Four affected individuals from a three-generation family underwent detailed ophthalmic examinations, including best-corrected visual acuity by Snellen E chart, slit-lamp biomicroscopy, indirect ophthalmoscopy under pupil dilatation, ocular B-ultrasonography, optical coherence tomography scans, and fundus autofluorescence. Targeted next-generation sequencing was performed to identify variants of the disease-causing gene for the proband, followed by co-segregation analysis using Sanger-DNA sequencing. Reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out to verify the effects of a variant on VCAN pre-mRNA splicing in the lymphocytes from the patients. We detected a novel heterozygous variant c.4004-4_c.4004-3delinsCA of VCAN in all four affected individuals. RT-PCR revealed that the novel variant caused an abnormal splicing in exon 8 of the VCAN and imbalanced versican transcripts. All four patients presented vitreous syneresis and bilateral retinal detachment occurring at different ages. The patients also showed different extents of visual defects and diverse clinical manifestations, including cataract, iris-lens synechiae, inverted papillae, and ectopic foveas. Our results expand the mutation spectrum of VCAN and further confirm that the splicing sites for exon 8 are mutation hot spots. Patients with WVR may present high phenotype variation; therefore, molecular analysis is very important for precise diagnosis of patients with inherited vitreoretinopathy.


Core cell cycle regulatory genes in rice and their expression profiles across the growth zone of the leaf.
Rice (Oryza sativa L.) as a model and crop plant with a sequenced genome offers an outstanding experimental system for discovering and functionally analyzing the major cell cycle control elements in a cereal species. In this study, we identified the core cell cycle genes in the rice genome through a hidden Markov model search and multiple alignments supported with the use of short protein sequence probes. In total we present 55 rice putative cell cycle genes with locus identity, chromosomal location, approximate chromosome position and EST accession number. These cell cycle genes include nine cyclin dependent-kinase (CDK) genes, 27 cyclin genes, one CKS gene, two RBR genes, nine E2F/DP/DEL genes, six KRP genes, and one WEE gene. We also provide characteristic protein sequence signatures encoded by CDK and cyclin gene variants. Promoter analysis by the FootPrinter program discovered several motifs in the regulatory region of the core cell cycle genes. As a first step towards functional characterization we performed transcript analysis by RT-PCR to determine gene specific variation in transcript levels along the rice leaves. The meristematic zone of the leaves where cells are actively dividing was identified based on kinematic analysis and flow cytometry. As expected, expression of the majority of cell cycle genes was exclusively associated with the meristematic region. However genes such as different D-type cyclins, DEL1, KRP1/3, and RBR2 were also expressed in leaf segments representing the transition zone in which cells start differentiation.


The differences in T and B cell subsets in thyroid of children with Graves' disease and Hashimoto's thyroiditis.
The differences between Graves' disease (GD) and Hashimoto's thyroiditis (HT) suggest that changes in the subsets of T cells may have an influence on the course of these reactions. This study included 90 children: 30 with GD, 30 with HT, and 30 healthy children as controls. After thyroidectomy, standard histological examinations and immunohistochemical reactions were performed in paraffin specimens with monoclonal antibodies against T cell markers CD3, CD4, CD8 as well as against CD79 alpha B cells. Ultrathin sections were examined under a transmission electron microscope. Autoimmune reaction in GD consisted of an increased number of CD4+ T cells (3.17±4.27%) and plasma cells (22.89±8.61%) producing thyroidstimulating hormone-receptors and stimulating thyrocytes to activity. The number of CD8+ T cells was increased in children with HT (20.54±0.68%) as compared with the controls (0.65±0.30%). The autoimmune reaction in the HT children showed antibody dependent cytotoxicity with a low number of CD4+ T cells and an increased number of CD8+ T cells in the thyroid tissue in comparison with that in the GD children and the controls. Plasma cells (31.65±9.11%) in this situation produced the antibodies involved in cytotoxic reactions against thyrocytes. Graves' disease is characterized by the increased number of CD4+ T cells and CD8+ T cells. Hashimoto's thyroiditis is characterized by the low number of CD4+ T cells and increased number of CD8+ T cells. CD8+ T cells have cytotoxic properties only in Hashimoto's thyroiditis.


Immunization with excreted-secreted antigens reduces tissue cyst formation in pigs.
It has been demonstrated that tachyzoite-pooled excreted-secreted antigens (ESAs) of Toxoplasma gondii are highly immunogenic and can be used in vaccine development. However, most of the information regarding protective immunity induced by immunization with ESAs is derived from studies using mouse model systems. These results cannot be extrapolated to pigs due to important differences in the susceptibility and immune response mechanisms between pigs and mice. We show that the immunization of pigs with ESAs emulsified in Freund's adjuvant induced not only a humoral immune response but also a cellular response. The cellular immune response was associated with the production of IFN-γ and IL-4. The humoral immune response was mainly directed against the antigens with molecular masses between 34 and 116 kDa. After intraperitoneal challenge with 10(7) T. gondii of the Gansu Jingtai strain (GJS) of tachyzoites, the immunized pigs remained clinically normal except for a brief low-grade fever (≤40.5 °C), while the control pigs developed clinical signs of toxoplasmosis (cough, anorexia, prostration, and high fever). At necropsy, visible lesions were found at multiple locations (enlarged mesenteric lymph nodes, an enlarged spleen with focal necrosis, and enlarged lungs with miliary or focal necrosis and off-white lesions) in all of the control pigs but not in the pigs that had been immunized. We also found that immunization with ESAs reduced tissue cyst formation in the muscle (P < 0.01). Our data demonstrate that immunization with ESAs can trigger a strong immune response against T. gondii infection in pigs.


Cyclopentenediones, inhibitors of farnesyl protein transferase and anti-tumor compounds, isolated from the fruit of Lindera erythrocarpa Makino.
Four cyclopentenediones, farnesyl protein transferase inhibitors, and anti-tumor compounds were isolated from the methanolic extract of the fruits of Lindera erythrocarpa Makino (Lauraceae). The structure of the compounds was determined by spectral data including NMR and mass spectrometry, and cyclopentenediones such as methyllinderone (1), methyllucidone (2), lucidone (3), and linderone (4) were identified by comparing their reported spectral data with that of the literature values. Compounds 1-4 inhibited farnesyl protein transferase with IC50 value of 55.3+/-4.1, 42+/-1.9, 103+/-5.1, and 40+/-3.5 microM, respectively. Isolated compounds also inhibited the growth of various human cancer cell lines in a dose-dependent manner. Especially, Compounds 1 and 2 selectively inhibited the growth of H-ras-transformed rat-2 cell lines in comparison with normal rat-2 cells with a GI50 value of 0.3 and 0.85 microM, respectively. Methyllucidone strongly inhibited the growth of human cancer cells and colon tumor xenografted in nude mice. The anti-tumor effects of the compound were further confirmed with caspase-3 activation and degradation of PARP. The results suggest that methyllucidone can be a potential anti-cancer agent against H-ras-transformed tumor and will also be a good lead molecule for the development of anti-tumor drug.


Effect of green tea extract loaded chitosan microparticles on facial skin: A split-face, double-blind, randomized placebo-controlled study.
The bioactivities of green tea extract were indicated to promote skin health in vitro. Few clinical studies reported on skin nourishment of topical applying green tea extract due to the limited skin absorption. This current study evaluated the clinical effectiveness and safety of green tea extract encapsulated chitosan microparticles (GTP) in emulsion base on a split-face, double-blind, randomized placebo-controlled study. Twenty-nine female volunteers were recruited into the study. They were randomly assigned to apply GTP and placebo creams on each half face for 8 weeks. The facial skin properties on both sides were monitored and evaluated every 2 weeks. The results revealed that skin elasticity (R2) of half face treated with GTP cream (0.748 ± 0.05) was superior to another that received placebo cream (0.722 ± 0.05) at 4th week. In addition, melanin index implying skin dullness of the half face that received GTP cream significantly improved within the 6th week after application (placebo =295.60 ± 58.81, GTP =282.70 ± 59.62). Most importantly, the photographs clearly indicated that the decreasing in facial wrinkles of volunteers applied with GTP cream was more than those applying placebo cream. Signs of skin irritation were not evident in both treatment and placebo cream groups. Based on study outcomes, the green tea extract encapsulated chitosan microparticles appear to be the promising active candidate for promoting skin elasticity and improving skin dullness and wrinkles.


Ancient mitochondrial genome depicts sheep maternal dispersal and migration in eastern Asia.
Sheep have been one of the most important groups of animals since ancient times. However, the knowledge of their migration routes and genetic relationships is still poorly understood. To investigate sheep maternal migration histories alongside Eurasian communications routes, in this study, we obtain mitochondrial genomes (mitogenomes) from 17 sheep remains in 6 Chinese sites and 1 Uzbekistan site dated 4429-3100 years before present (BP). By obtaining the mitogenomes from the sheep (4429-3556 years old) found in Tongtian Cave site in Xinjiang, Altai region of northwest China, our results support the emergence of haplogroup C sheep in Xinjiang as early as 4429-3556 BP. The combined phylogenetic analyses with extant ancient and modern sheep mitogenomes suggest that the Uzbekistan-Altai region might have been a migration hub for early sheep in eastern Asia. At least two migration events have taken place for sheep crossing Eurasia to China, one passing by Uzbekistan and Northwest China to the middle and lower reaches of the Yellow River at approximately 4000 BP and another following the Altai region to middle Inner Mongolia from 4429 to 2500 BP. Overall, this study provides further evidence for early sheep utilization and migration patterns in eastern Asia.


Distinct and Overlapping Roles of Hippo Effectors YAP and TAZ During Human and Mouse Hepatocarcinogenesis.
Yes-associated protein (YAP) and its paralog transcriptional co-activator with post synaptic density protein, drosophila disc large tumor suppressor and zonula occludens-1-binding motif (TAZ) are 2 co-activators downstream of Hippo tumor-suppressor cascade. Both have been implicated in the development of hepatocellular carcinoma (HCC). However, whether YAP and TAZ have distinct or overlapping functions during hepatocarcinogenesis remains unknown. Expression patterns of YAP and TAZ were analyzed in human HCC samples. The requirement of Yap and/or Taz in protein kinase B (Akt)/ neuroblastoma RAS viral oncogene homolog (NRas) -driven liver tumorigenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout mice. Transcriptional programs regulated by YAP and/or TAZ were identified via RNA sequencing. We found that in human HCC samples, an almost ubiquitous activation of YAP or TAZ occurs, underlying their role in this tumor type. Intriguingly, 70% of HCC samples showed only nuclear YAP or TAZ immunoreactivity. In the Akt/NRas liver tumor model, where nuclear Yap and Taz can be detected readily, deletion of Yap or Taz alone only mildly delayed liver tumor development, whereas their concomitant ablation strongly inhibited tumor cell proliferation and significantly suppressed Akt/NRas-driven hepatocarcinogenesis. In HCC cell lines, silencing of either YAP or TAZ led to decreased expression of both overlapping and distinct sets of genes, with the most prominent gene signatures related to cell-cycle progression and DNA replication. YAP and TAZ have overlapping and distinct roles in hepatocarcinogenesis. HCCs may display unique activation of YAP or TAZ, thus relying on either YAP or TAZ for their growth.


Toxicological evaluation of ferrous N-carbamylglycinate chelate: Acute, Sub-acute toxicity and mutagenicity.
Iron is an essential trace element that is vital important in various biological process. A deficiency in iron could induce public health problem e.g. anaemia, while an overload could induce ROS production, lipid peroxidation and DNA bases modifications. In the present study, a new iron fortifier was synthesized, and its acute/sub-acute toxicity was investigated. According to the improved Karber's method, the median lethal dose (LD50) of the ferrous N-carbamylglycinate in SD rat was 3.02 g/kg and the 95% confidence intervals were between 2.78 and 3.31 g/kg. No biologically significant or test substance-related differences were observed in body weights, feed consumption, clinical signs, organ weights, histopathology, ophthalmology, hematology, and clinical chemistry parameters in any of the treatment groups of ferrous N-carbamylglycinate at target concentrations corresponding to 150, 300, and 600 mg/kg/day for 28 days. The no observed adverse effect level (NOAEL) for ferrous N-carbamylglycinate was at least 600 mg/kg b.w. day in rats. In addition, no evidence of mutagenicity was found, either in vitro in bacterial reverse mutation assay or in vivo in mice bone marrow micronucleus assay and sperm shape abnormality assay. On the basis of our findings, we conclude that ferrous N-carbamylglycinate is a low-toxic substance with no genotoxicity.


Utilization of the metal-cyano complex tetracyanonickelate (II) by Azotobacter vinelandii.
The ability of Azotobacter vinelandii, a N(2)-fixing bacterium, to biodegrade tetracyanonickelate (TCN) was evaluated. The amounts of TCN were measured spectrophotometrically. Ammonia was determined colorimetrically by the indophenol method. The produced methane from TCN conversion by A. vinelandii was detected by gas chromatography. Results showed that A. vinelandii was able to biodegrade 1 mmol l(-1) of TCN. Ammonia and methane were detected during the process of TCN degradation. Effects of exogenous nitrogen sources on TCN degradation were addressed in this study. Results revealed that the addition of ammonia (1, 5 and 10 mmol l(-1)) into the reaction mixtures caused decrease of TCN degradation rate during a 24-h incubation period. This inhibition was also observed when nitrite (5 and 10 mmol l(-1)) was added, whereas TCN degradation still proceeded after the addition of nitrate at the same concentrations. Furthermore, the rate of TCN utilization was strikingly enhanced when 0.8% of glucose was added. Azotobacter vinelandii can degrade 1 mmol l(-1) of TCN into ammonia and methane. However, the inhibitory effects of exogenous ammonia and nitrite on TCN degradation by this bacterium were found in this study. This is the first report defining the capability of A. vinelandii to degrade TCN. This bacterium might have potential value in applied strategies for removing metal-cyano wastes. Furthermore, these findings would be helpful in designing a practical system inoculated with A. vinelandii for the treatment of TCN.


Solubilization of 6-oxybenzo(a)pyrene radical by caffeine and DNA as studied by magnetic resonance. Observation of intermolecular charge transfer.
Crystals of 6-oxybenzo(a)pyrene free radical, formed chemically from the hydroxy derivative of the carcinogen benzo(a)pyrene, can be solubilized in aqueous solutions of DNA and of caffeine. ESR spectral evidence indicate that the radicals exist as dispersed monomers associated with DNA and with caffeine. Comparison of NMR spin-lattice and spin-spin relaxation times in the protons of caffeine has given direct evidence that a part of the unpaired electron (at least 10(-4)) is transferred from the radical to the associated caffeine molecule. Simple consideration of Mulliken's charge transfer theory, however, leads to the conclusion that the intermolecular charge transfer is not likely to be a major source of stabilization energy of the complex.


The Near-Death Experience Content (NDE-C) scale: Development and psychometric validation.
As interest grows in near-death experiences (NDEs), it is increasingly important to accurately identify them to facilitate empirical research and reproducibility among assessors. We aimed (1) to reassess the psychometric properties of the NDE scale developed by Greyson (1983) and (2) to validate the Near-Death Experience Content (NDE-C) scale that quantifies NDEs in a more complete way. Internal consistency, construct and concurrent validity analyses were performed on the NDE scale. Based on those results and the most recent empirical evidence, we then developed a new 20-item scale. Internal consistency, explanatory and confirmatory factor, concurrent and discriminant validity analyses were conducted. Results revealed (1) a series of weaknesses in the NDE scale, (2) a 5-factor structure covering relevant dimensions and the very good psychometric properties of the NDE-C scale, including very good internal consistency (Cronbach α = 0.85) and concurrent validity (correlations above 0.76). This new reliable scale should facilitate future research.


Serum D-lactate levels as a predictor of intestinal ischemia-reperfusion injury.
Currently, no serum marker has proved helpful in diagnosing intestinal ischemia and reperfusion (I/R) injury. An experimental study was conducted to determine the value of serum D-lactate in detecting intestinal I/R injury. Thirty New Zealand White rabbits were divided into three groups of 10 animals each: sham-operation controls (S); I/R; and I/R plus mannitol treatment (M). Serum samples were obtained before operation (T0), at the end of the ischemic period (T1), after the first 30 min of reperfusion (T2), and at the end of the reperfusion period (T3). In Group S, mean D-lactate levels for T0, T1, and T2 were 0 microgram/dl, while T3 was 5. 8 +/- 4.7 micrograms/dl. Before the operation (T0), serum mean D-lactate levels were 0 microgram/dl in all groups (S, I/R, M). Levels increased after 1 h of ischemia (T1) in groups I/R (83.5 +/- 25.6 micrograms/dl) and M (89.8 +/- 19.9 micrograms/dl), but not in group S (0 microgram/dl). The mean T2 level in group I/R (231.6 +/- 78.6 micrograms/dl) was statistically higher than in group M (140.1 +/- 53.5 micrograms/dl) (P = 0.007). At the end of the reperfusion period, the mean T3 level in group I/R (698.4 +/- 360.4 micrograms/dl) was significantly higher than in group M (158.7 +/- 61.4 micrograms/dl) (P = 0.000). In group I/R, mean D-lactate levels changed significantly at each time point (T1 vs T2, P = 0.001; T2 vs T3, P = 0.004). However, in group M the increase from T1 to T2 was significant (P = 0.012), but that from T2 to T3 was not (P = 0.293). As a result, the mean T3 level was significantly higher than the T2 level in group I/R (P = 0.004), but not in group M. This study confirmed a significance rise in D-lactate levels in animals with I/R injury compared to sham-operated and I/R injury plus M treatment. We suggest that serum D-lactate levels could be a useful marker of intestinal I/R injury before laparatomy.


Information-hungry and disempowered: a qualitative study of women and their partners' experiences of severe postpartum haemorrhage.
to explore how severe postpartum haemorrhage (PPH) and its management is experienced by women and their partners, and how they later view events. interpretive phenomenological qualitative study with semi-structured interviews. in-depth interviews were conducted in participants' homes and focused on experiences of PPH in hospital and post-discharge. nine women who had experienced severe PPH and six partners. this study demonstrates the stressful and emotional nature of severe PPH and extends the literature by considering partners' perspectives. Women and men had different experiences and information needs, but interviewees often shared a common desire for help to understand past events. A dominant theme of communication difficulties, and two subthemes, disempowerment and information-deprivation arose strongly from the data. Communication difficulties were understandable during the emergency but were frustrating and upsetting in postpartum care and the longer term. research is needed to develop better communication and supportive strategies, which might avoid the sense of disempowerment in this potentially vulnerable population. Different information and support needs for women and men should be considered whatever policies are implemented.


Two decades of risk factors and transfusion-transmissible infections in Dutch blood donors.
Risk behavior-based donor selection procedures are widely used to mitigate the risk of transfusion-transmissible infections (TTIs), but their effectiveness is disputed in countries with low residual risks of TTIs. In 1995 to 2014, Dutch blood donors infected with hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), or syphilis were interviewed by trained medical counselors to identify risk factors associated with TTIs. Trends in the prevalence and incidence of TTIs were analyzed using binomial regression models. A total of 972 new donors and 381 repeat donors had TTIs. New donors had higher rates of TTIs compared to repeat donors. Although the HBV and HCV prevalence gradually decreased over time, the incidence of all five TTIs remained stable during the past two decades. In new donors the TTIs had the following risk profiles: "blood-blood contact" for HCV, "unprotected sex" for HIV and syphilis, and "country of birth" for HBV and HTLV. In infected repeat donors, sexual risk factors predominated for all TTIs. At posttest counseling, 28% of infected repeat donors admitted to risk factors leading to permanent donor exclusion if revealed during the donor selection procedure (predominantly male-to-male sex and recent diagnosis of syphilis). The prevalence and incidence of TTIs among Dutch blood donors are six- to 60-fold lower than in the general Dutch population, illustrating the effectiveness of donor selection procedures. However, at least a quarter of infected donors appeared noncompliant to the donor health questionnaire (DHQ), suggesting that DHQs, or the way donor questioning is implemented, can be improved.


Estimating time-to-contact when vision is impaired.
Often, we have to rely on limited information when judging time-to-contact (TTC), as for example, when driving in foul weather, or in situations where we would need reading glasses but do not have them handy. However, most existing studies on the ability to judge TTC have worked with optimal visual stimuli. In a prediction motion task, we explored to what extent TTC estimation is affected by visual stimulus degradation. A simple computer-simulated object approached the observer at constant speed either with clear or impaired vision. It was occluded after 1 or 1.5 s. The observers extrapolated the object's motion and pressed a button when they thought the object would have collided with them. We found that dioptric blur and simulated snowfall shortened TTC-estimates. Contrast reduction produced by a virtual semi-transparent mask lengthened TTC estimates, which could be the result of distance overestimation or speed underestimation induced by the lower contrast or the increased luminance of the mask. We additionally explored the potential influence of arousal and valence, although they played a minor role for basic TTC estimation. Our findings suggest that vision impairments have adverse effects on TTC estimation, depending on the specific type of degradation and the changes of the visual environmental cues which they cause.


Sex-dependent Effects of the Drugs of Abuse Amphetamine and the Smart Drug 3,4-Methylenedioxypyrovalerone on Fear Memory Generalization in Rats.
In recent years there has been an increase in the development of new synthetic drugs, among which the "bath salt" 3,4-methylenedioxypyrovalerone (MDPV), a psychostimulant with a mechanism of action similar to those of cocaine and amphetamine, stands out. Drugs of abuse have been consistently shown to affect memory function in male rodents. We have recently shown that amphetamine and MDPV induce generalization of fear memory in an inhibitory avoidance discrimination task in male rats. Although abuse of illicit drugs is more prevalent in men than in women, several studies have demonstrated that females are more vulnerable to the effects of drugs of abuse than males and the effects caused by substance dependence on memory in females are still under-investigated. Thus, we examined the effects of subchronic amphetamine or MDPV administrations on memory in a contextual fear conditioning/generalization paradigm in adult male and female rats. Animals were given daily subchronic injections of the drugs, starting 6 days prior to the beginning of the behavioral procedures until the end of the paradigm. On day 1 of the experimental protocol, all rats were exposed to a safe context and, the day after, to a slightly different chamber where they received an unsignaled footshock. Twenty-four and forty-eight hours later, freezing behavior and emission of 22 kHz-ultrasonic vocalizations (USVs) were measured in the two different contexts to assess fear memory retention and generalization. Our results indicate that MDPV treatment altered freezing in both sexes, USVs were affected by amphetamine in males while by MDPV in females.


Quadruple-negative breast cancer: novel implications for a new disease.
Based on the androgen receptor (AR) expression, triple-negative breast cancer (TNBC) can be subdivided into AR-positive TNBC and AR-negative TNBC, also known as quadruple-negative breast cancer (QNBC). QNBC characterization and treatment is fraught with many challenges. In QNBC, there is a greater paucity of prognostic biomarkers and therapeutic targets than AR-positive TNBC. Although the prognostic role of AR in TNBC remains controversial, many studies revealed that a lack of AR expression confers a more aggressive disease course. Literature characterizing QNBC tumor biology and uncovering novel biomarkers for improved management of the disease remains scarce. In this comprehensive review, we summarize the current QNBC landscape and propose avenues for future research, suggesting potential biomarkers and therapeutic strategies that warrant investigation.


Volume changes after stereotactic LINAC radiotherapy in vestibular schwannoma: control rate and growth patterns.
The purpose of this study was to evaluate the control rate of vestibular schwannomas (VS) after treatment with linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) or radiotherapy (SRT) by using a validated volumetric measuring tool. Volume-based studies on prognosis after LINAC-based SRS or SRT for VS are reported scarcely. In addition, growth patterns and risk factors predicting treatment failure were analyzed. Retrospectively, 37 VS patients treated with LINAC based SRS or SRT were analyzed. Baseline and follow-up magnetic resonance imaging scans were analyzed with volume measurements on contrast enhanced T1-weighted magnetic resonance imaging. Absence of intervention after radiotherapy was defined as "no additional intervention group, " absence of radiological growth was defined as "radiological control group. " Significant growth was defined as a volume change of 19.7% or more, as calculated in a previous study. The cumulative 4-year probability of no additional intervention was 96.4% ± 0.03; the 4-year radiological control probability was 85.4% ± 0.1). The median follow-up was 40 months. Overall, shrinkage was seen in 65%, stable VS in 22%, and growth in 13%. In 54% of all patients, transient swelling was observed. No prognostic factors were found regarding VS growth. Previous treatment and SRS were associated with transient swelling significantly. Good control rates are reported for LINAC based SRS or SRT in VS, in which the lower rate of radiological growth control is attributed to the use of the more sensitive volume measurements. Transient swelling after radiosurgery is a common phenomenon and should not be mistaken for treatment failure. Previous treatment and SRS were significantly associated with transient swelling.


Identification of a non peptidic RANTES antagonist.
A series of phenothiazines demonstrating inhibition of RANTES binding to THP-1 cell membranes has been identified. The lead compound RP23618 (IC50 = 3 microM) was found to inhibit specific binding of 125I-RANTES, but not 125I-MCP-1 to THP-1 cell membranes and furthermore to antagonize RANTES, but not MCP-1-induced chemotaxis of THP-1 cells.


Sequence-dependence and prediction of nucleotide solvent accessibility in double stranded DNA.
Solvent accessibility of amino acid residues in proteins has been widely studied and many methods for its prediction from sequence and evolutionary information are available. Some of the advantages of studying amino acid solvent accessibility also apply to DNA. However, currently there are no methods to estimate the solvent accessibility of nucleotides, as most works on DNA structures have focused on elastic deformations and other structural attributes. In this work, an attempt has been made to analyze the distribution of different nucleotides in various accessibility ranges. Effect of neighboring nucleotides on the predictability of exposure has been evaluated by developing a linear perceptron model that takes sequence information as the input. Five different types of solvent accessibility (overall nucleotide, side chain, main chain, polar and non-polar) have been predicted. From the analysis, it is observed that Thymine stands out in terms of its higher exposed surface area, particularly its side chain and non-polar atoms. It is also concluded that the solvent accessibility of a nucleotide strongly depends on its sequence neighbors and can be predicted with fair success using this information.


Efficient methods to generate reproducible mass spectra in matrix-assisted laser desorption ionization of peptides.
In our previous matrix-assisted laser desorption ionization (MALDI) studies of peptides, we found that their mass spectra were virtually determined by the effective temperature in the early matrix plume, Tearly, when samples were rather homogeneous. This empirical rule allowed acquisition of quantitatively reproducible spectra. A difficulty in utilizing this rule was the complicated spectral treatment needed to get Tearly. In this work, we found another empirical rule that the total number of particles hitting the detector, or TIC, was a good measure of the spectral temperature and, hence, selection of spectra with the same TIC resulted in reproducible spectra. We also succeeded in obtaining reproducible spectra throughout a measurement by controlling TIC near a preset value through feedback adjustment of laser pulse energy. Both TIC selection and TIC control substantially reduced the shot-to-shot spectral variation in a spot, spot-to-spot variation in a sample, and even sample-to-sample variation in MALDI using α-cyano-4-hydroxycinnamic acid or 2,5-dihydroxybenzoic acid as matrix. Based on the utilization of acquired data, TIC control was more efficient than TIC selection by an order of magnitude. Both techniques produced calibration curves with excellent linearity, suggesting their utility in quantification of peptides.


A crystallization apparatus for temperature-controlled flow-cell dialysis with real-time visualization.
Many instrumentation developments in crystallization have concentrated on massive parallelization assays and reduction of sample volume per experiment to find initial crystallization conditions. Yet improving the size and diffraction quality of the crystals for diffraction studies often requires decoupling of crystal nucleation and growth. This in turn requires the control of variables such as precipitant and protein concentration, equilibration rate, and temperature, which are all difficult parameters to control in the existing setups. The success of the temperature-controlled batch method, originally developed to grow very large crystals for neutron crystallography, demonstrated that the rational optimization of crystal growth has potential in structural biology. A temperature-controlled dialysis button has been developed for our previous device, and a prototype of an integrated apparatus for the rational optimization of crystal growth by mapping and manipulating temperature-precipitant concentration phase diagrams has been constructed. The presented approach differs from the current paradigm, since it involves serial instead of parallel experiments, exploring multiple crystallization conditions with the same protein sample. The sample is not consumed in the experiment and the conditions can be changed in a reversible fashion, using dialysis with a flowing precipitant reservoir as well as precise temperature control. The control software allows visualization of the crystals, as well as control of the temperature and composition of the crystallization solution. The rational crystallization optimization strategies presented here allow tailoring of crystal size, morphology and diffraction quality, significantly reducing the time, effort and amount of expensive protein material required for structure determination.


Embryological evidence substantiates the subcoxal theory on the origin of pleuron in insects.
The lateral body plate pleuron is a significant structure in insects that contributes to the development and elaboration of wings and limbs (appendages). Although the pleuron is thought to originate from the proximal-most appendicular segment, the subcoxa, details remain unclear, and the morphological boundary between the dorsal body plate tergum and appendage (BTA) has not been clearly specified. Employing low-vacuum scanning electron microscopy (SEM) and the nano-suit method for SEM, we followed, in detail, the development of the thoracic segments of the two-spotted cricket Gryllus bimaculatus and succeeded in clearly defining the BTA. This study demonstrates the subcoxal origin of the pleuron, suggests the tergal origin of spiracles, and reveals that the wing proper originates exclusively from the tergum, whereas the wing hinge and direct muscles may be appendicular in origin, suggesting the dual origin (i.e., tergal plus appendicular origin) of wings.


Development as Liberation.
At a point in history where the worlds social and ecological boundaries are at a true testing point, this article presents some thoughts and questions around the tensions between reformist and revolutionary actions and ends in presenting dreaming as a tool towards emancipation. Through these thoughts, collective action is a central cog towards meaningful progress.


Independence of heritable influences on the food intake of free-living humans.
The time of day of meal ingestion, the number of people present at the meal, the subjective state of hunger, and the estimated before-meal contents in the stomach have been established as influences on the amount eaten in a meal and these influences have been shown to be heritable. Because these factors intercorrelate, the calculated heritabilities for some of these variables might result indirectly from their covariation with one of the other heritable variables. The independence of the heritability of the influence of these four factors was investigated with 110 identical and 102 fraternal same-sex and 53 fraternal mixed-sex adult twin pairs who were paid to maintain 7-d food-intake diaries. From the diary reports, the meal sizes were calculated and subjected to multiple regression analysis using the estimated before-meal stomach contents, the reported number of other people present, the subjective hunger ratings, and the time of day of the meal as predictors. Linear structural modeling was applied to the beta-coefficients from the multiple regression to investigate whether the heritability of the influences of these four variables was independent. Significant genetic effects were found for the beta-coefficients for all four variables, indicating that the heritability of their relationship with intake is to some extent independent and heritable. This suggests that influences of multiple factors on intake are influenced by the genes and become part of the total package of genetically determined physiologic, sociocultural, and psychological processes that regulate energy balance.


New Insulating Antiferromagnetic Quaternary Iridates MLa10Ir4O24 (M = Sr, Ba).
Recently, oxides of Ir(4+) have received renewed attention in the condensed matter physics community, as it has been reported that certain iridates have a strongly spin-orbital coupled (SOC) electronic state, J eff = ½, that defines the electronic and magnetic properties. The canonical example is the Ruddlesden-Popper compound Sr2IrO4, which has been suggested as a potential route to a new class of high temperature superconductor due to the formal analogy between J eff = ½ and the S = ½ state of the cuprate superconductors. The quest for other iridium oxides that present tests of the underlying SOC physics is underway. In this spirit, here we report the synthesis and physical properties of two new quaternary tetravalent iridates, MLa10Ir4O24 (M = Sr, Ba). The crystal structure of both compounds features isolated IrO6 octahedra in which the electronic configuration of Ir is d(5). Both compounds order antiferromagnetically despite the lack of obvious superexchange pathways, and resistivity measurement shows that SrLa10Ir4O24 is an insulator.


Prognostic Indices and Mortality Prediction in COPD Caused by Biomass Smoke Exposure.
Little is known about survival and prognostic factors in chronic obstructive pulmonary disease (COPD) due to biomass smoke exposure (BS-COPD). (1) To determine the value of two indices of COPD severity: BODEx (body mass index, obstruction, dyspnea, and previous severe exacerbations) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) categories system (ABCD) to predict all-cause mortality in BS-COPD, compared with COPD due to tobacco (T-COPD); (2) to verify the usefulness of 2 comorbidity indices, Charlson index and COTE (COPD comorbidity index); and (3) to put side by side the value of these indices. 612 consecutive COPD patients were retrospectively studied. Prognostic factors were evaluated taking into account the exposure to biomass or tobacco smoke. The relative predictive values of the prognostic indices were compared using receiver-operating characteristic analysis. Mortality in the BS-COPD and T-COPD groups was not significantly different, when sex was taken into account. BODEx, Charlson and COTE indices-but not type of exposure-predicted mortality in multivariate analysis. The value of the C-statistic for the BODEx index was not different than that of GOLD ABCD for BS-COPD, but was higher for T-COPD. The discriminatory value of the Charlson index was higher than that of COTE for BS-COPD, but no significant differences were found for T-COPD. Multidimensional indices of COPD severity and comorbidity predict all-cause mortality in BS-COPD. The behavior of the different indices is different for BS-COPD and T-COPD.


Possible worlds truth table task.
In this paper, a novel experimental task is developed for testing the highly influential, but experimentally underexplored, possible worlds account of conditionals (Lewis, 1973; Stalnaker, 1968). In Experiment 1, this new task is used to test both indicative and subjunctive conditionals. For indicative conditionals, five competing truth tables are compared, including the previously untested, multi-dimensional possible worlds semantics of Bradley (2012). In Experiment 2, these results are replicated and it is shown that they cannot be accounted for by an alternative hypothesis proposed by our reviewers. In Experiment 3, individual variation in truth assignments of indicative conditionals is investigated via Bayesian mixture models that classify participants as following one of several competing truth tables. As a novelty of this study, it is found that a possible worlds semantics of Lewis and Stalnaker is capable of accounting for participants' aggregate truth value assignments in this task. Applied to indicative conditionals, we show across three experiments, that the theory both captures participants' truth values at the aggregate level (Experiments 1 and 2) and that it makes up the largest subgroup in the analysis of individual variation in our experimental paradigm (Experiment 3).


Clinical experience with dofetilide in the treatment of patients with atrial fibrillation.
Dofetilide for Treatment of AF. Dofetilide is the newest drug approved by the United States Food and Drug Administration for the treatment of patients with atrial fibrillation (AF). Few data on the efficacy and safety of dofetilide in a diverse group of patients are available. The aim of this study was to evaluate the results of dofetilide in a consecutive series of 69 patients with AF. Sixty-nine patients with persistent (n = 53) or paroxysmal (n = 16) AF were administered dofetilide in-hospital. Prior to starting dofetilide, all patients had been adequately anticoagulated, and concomitant agents contraindicated in the presence of dofetilide were discontinued. Heart rhythms were monitored continuously by telemetry in all patients. The initial dose, which was determined using the Cockroft-Gault calculated creatinine clearance, was 500 microg bid, 250 microg bid, and 125 microg bid in 51, 13, and 5 patients, respectively. Reductions in subsequent dosage occurred in 12 patients, 4 for QT prolongation. Dofetilide was discontinued in-hospital in 7 patients, 2 for adverse arrhythmic events and 3 for unacceptable QT prolongation. Twenty-seven (63%) of 43 patients in AF converted spontaneously to sinus rhythm. Fifty-eight patients were discharged receiving dofetilide treatment and were followed as outpatients for 21 +/- 7 months. One third of patients continued to take dofetilide at 1 year. One patient had a cardiac arrest 1 day after hospital discharge. Dofetilide is a well-tolerated antiarrhythmic drug with a high conversion rate of AF to sinus rhythm. One third of patients maintained sinus rhythm at 1 year. Proarrhythmia can occur and initiation of therapy must be performed in-hospital.


Complications of anterior craniofacial resection.
The complications associated with anterior craniofacial resections for benign and malignant tumors were reviewed in 104 patients treated between January 1981 and June 1996. Information regarding patient characteristics, histologic type, history of prior therapy, extent of the disease, extent of surgical procedure, and type of reconstruction were entered in a microcomputer database. To better understand and stage postoperative complications, we divided them into early (<14 days) and late (>14 days) according to the time of presentation, into major and minor depending on the morbidity potential of complication, and into local and systemic ones. Comparison between risk factors associated with complications was made using chi-square analysis with Yates' correction for continuity. Survival analysis was performed using the Kaplan-Meier product limit method. There were 8 (7.6%) postoperative deaths, with only 1 occurring from systemic complications. Complications occurred in 53 (48.6%) patients. Local major complications occurred in 49 (45%) patients, local minor in 29 (26.6%), and systemic in 11 (10%). Early complications occurred in 40 (38.5%) patients and late complications in 13 (12.5%) patients. These complications developed during a period ranging from 1 day to 5 months. More than one complication occurred in a number of patients. Bacterial contamination leading to local septic complications was the principal cause of morbidity, accounting for 54.7% (29/53) of complications. Major complications included meningitis in 8 patients associated with cerebrospinal fluid leak in 7, cerebral abscess in 2, sepsis in 1, and subdural hemorrhage in 1, all of which resulted in death except for one case. The extent of the craniofacial resection (p = .011) was the most important factor associated with major complications. Invasion of the dura and the type of reconstruction of the anterior skull base were the most important factors related to cerebrospinal fluid leakage (p = .048 and p = .032) and meningitis (p = .011). Contemporary surgical approaches and methods of reconstruction have enabled skull base surgeons to extend their cranial base resections and increase the 5-year survival rates of patients. Nevertheless, significant complications persist. Knowledge and high index of suspicion together with early recognition of these complications are essential for effective management of patients undergoing craniofacial resection. The factors related to major complications found in this study stressed the need to develop more effective methods to prevent contamination of intracranial structures.


Oral Immunization of Rabbits with S. enterica Typhimurium Expressing Neisseria gonorrhoeae Filamentous Phage Φ6 Induces Bactericidal Antibodies Against N. gonorrhoeae.
All Neisseria gonorrhoeae strains whose DNA sequences have been determined possess filamentous phage DNA sequences. To ascertain if phage encoded proteins could form the basis of a gonococcal vaccine, rabbits were orally infected with S. enterica Typhimurium strain χ3987 harboring phagemid NgoΦ6 fm. The elicited sera contained large quantities of anti-phage IgG and IgA antibodies that bound to the surface of N. gonorrhoeae cells, as shown by indirect fluorescent analysis and flow cytometry. The elicited sera was able to bind to several phage proteins. The sera also had bactericidal activity. These data demonstrate that N. gonorrhoeae filamentous phage can induce antibodies with anti-gonococcal activity and that phage proteins may be a candidate for vaccine development.


Peptide discovery using bacterial display and flow cytometry.
Peptides are increasingly used as therapeutic and diagnostic agents. The combination of bacterial cell-surface display peptide libraries with magnetic- and fluorescence-activated cell sorting technologies provides an efficient and highly effective methodology to identify and engineer peptides for a growing number of molecular recognition applications. Here, detailed protocols for both the generation and screening of bacterial display peptide libraries are presented. The methods described enable the discovery and evolutionary optimization of protein-binding peptides, cell-specific peptides, and enzyme substrates for diverse biotechnology applications.


The effect of a sewage treatment plant effluent on the faecal coliforms and enterococci populations of the reception river waters.
A rural sewage treatment plant and the effect of its effluent on the enterococci and faecal coliforms populations of the receiving river waters was evaluated. The enumeration of bacteria was performed by membrane filtration. Diversity and population similarity were analysed using the PhP-plates system. The treatment plant reduces the number of enterococci and faecal coliforms to values similar to those observed upstream. All water samples showed a high diversity for both bacterial populations. A high similarity in the composition and structure, was detected among all the samples. The impact of the disposal of treated sewage on the river did not modify the composition of either bacterial populations in the river water. The biochemical phenotyping of bacterial populations is a reliable tool for ecological and biodiversity studies. The obtained results provide a better understanding of the sewage treatment process and the impact of the treated sewage effluents in the environment.


New ways of looking at memory function: certain traumatic memories function like viruses, replicating themselves.
By the process of natural selection, life on earth spreads in all directions, finding niches favorable for survival. Some niches are harmful to another plant or animal (parasitism). This universal survival strategy applies to all living things, and apparently even non-living things such as viruses and prions. The same pattern may occur with immaterial entities such as memories. Traumatic memories mimic virus behavior in many ways such as infecting, spreading, occasionally becoming latent, and even reproducing themselves. Patients with past traumatic experiences are still "infected" with pathogenic memories. The experience remains ever-present in the patient's neural pathways and may even grow via a feedback loop in which each episode of remembering produces a stress hormone response. Under this model, doctors might view and treat patients with a history of trauma as persons infected with latent memories which periodically break out and cause new damage.


Hypotonicity promotes epithelial gap closure by lamellipodial protrusion.
The closure of gaps within epithelia is an essential part of many physiological and pathological processes, such as embryonic development, organ remodeling and wound healing. Emerging evidence proved that the physical microenvironment plays important roles in cell behaviors. However, the effect of osmolarity of extracellular medium on gap closure is least understood. Using a gap closure model of epithelial cells, we found that hypotonic condition significantly facilitated the process of gap closure. Moreover, instead of actomyosin ring, enhanced migration leading by lamellipodia primarily contributed to the rapid gap closure in hypotonic condition. These findings provide insights for understanding the physiology of epithelial gap closure.


Thyroid and parathyroid ultrasonography.
The introduction of high-resolution real-time small-parts sonography has made imaging the superficial structures of the neck a practical procedure. This article reviews the normal anatomy of the neck as well as the benign and malignant diseases affecting the thyroid and parathyroid glands.


Observers' proficiency at identifying pretense acts based on behavioral cues.
Discriminating what is pretense from what is real is a fundamental problem in development. Research has addressed the proficiency with which adults and children discriminate between play fighting and real fighting, and yet none (to our knowledge) has investigated discrimination of other kinds of pretense and real acts. In addition, little is known about what aspects of pretender behavior (as opposed to pretend content) might cue pretense interpretations. In two experiments, 8-20 s clips showing pretense and real snack behaviors were presented to adult and child participants. All participants distinguished between pretense and real behaviors at better than chance level. Furthermore, certain features (specific looking patterns and mistimed behaviors) were most prominent in the videotapes that were most often correctly identified. This provides empirical support for the suggestion that these cues, as opposed to more commonly cited cues, like smiles, might serve as important indicators of pretense for children and adults.


Stabilization of bovine intestine alkaline phosphatase by sugars.
Bovine intestine alkaline phosphatase (BIALP) is widely used as a signaling enzyme in sensitive assays such as enzyme immunoassay. In this study, we evaluated the effects of sugars on the kinetic stability of BIALP in the hydrolysis of p-nitrophenylphosphate (pNPP). The temperatures reducing initial activity by 50% in a 30-min incubation, T(50), of BIALP with 1.0 M disaccharide (sucrose and trehalose) or 2.0 M monosaccharide (glucose and fructose) were 55.0-55.5 °C, 4.7-5.2 °C higher than without sugar (50.3±0.1 °C). The T(50) of BIALP increased to 58.4±0.3 °C when the trehalose concentration was from 1.0 to 1.5 M, but did not change when the glucose concentration was from 2.0 to 3.0 M. Thermodynamic analysis revealed that the stabilization of BIALP by sugars was driven by the increase in the enthalpy change of activation for thermal inactivation of BIALP. No sugars affected the k(cat) of BIALP in the hydrolysis of pNPP. These results suggest that not only trehalose, which is considered the most effective stabilizer of enzymes, but also sucrose, glucose, and fructose can be used as stabilizers of BIALP.


The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition.
Benign prostatic hyperplasia (BPH) is an age-related disease in men. Mesenchymal /stromal and epithelial cells interactions are essential to prostate functions. In this study, human nonmalignant prostate epithelial RWPE-1 cells were cocultured with testosterone (TE) -exposed prostate stromal fibroblasts WPMY-1 cells (TE-WPMY-1). The survival rate, epithelial-mesenchymal transition (EMT) and collagen deposition of RWPE-1 were observed. The expression profiles of circRNAs, lncRNAs and mRNAs in WPMY-1-derived exosome-like vesicles (WPMY-1-exo) were explored by high-throughput RNA sequencing. Firstly, both TE-WPMY-1 and TE-WPMY-1-exo significantly promoted RWPE-1 cells proliferation. Secondly, 41 circRNAs, 132 lncRNAs and 1057 mRNAs were differentially expressed (DE) between TE-WPMY-1-exo and the control. Functional enrichment analyses, co-expression analyses and quantitative real-time PCR verification showed that the DE RNAs played important roles in cell proliferation, structure, phenotype and fibrosis. Lastly, blocking WPMY-1-exo biogenesis/release by GW4869 can attenuate TE-WPMY-1-stimulated RWPE-1 cells EMT and collagen deposition. Taken together, our results indicated that WPMY-1-exo modulated the phenotypes changes and collagen deposition of prostate epithelial cells. It provided a novel basis for understanding the underlying mechanisms of RWPE-1 cells EMT and fibrosis induced by WPMY-1 in BPH.


Brain sodium uptake after choroid plexectomy.
When in a (control) series of rats brain sodium uptake (BSU) -- as calculated from estimated radioactivities of brain and blood following the injection of [24Na]sodium chloride 30 min and [22Na]sodium chloride one minute before killing -- was plotted against average arterial blood pressure of the animals during the 30 min survival period, a linear dependence of BSU on blood pressure was observed. In another series of animals, in which the choroid plexuses of the fourth and both lateral ventricles had been removed, the regression line showed the same slope, but a significantly lower intercept. On the other hand, a series of rats which had been subjected to a sham operation without removal of the choroid plexuses, showed a regression line not different from the control series. The results indicate that probably the blood pressure independent component of brain sodium uptake, as represented by the intercept of the regression line, for the greater part constitutes cerebrospinal fluid secretion by the choroid plexus.


Degradation of organic pollutants in Mediterranean forest soils amended with sewage sludge.
The degradation of two groups of organic pollutants in three different Mediterranean forest soils amended with sewage sludge was studied for nine months. The sewage sludge produced by a domestic water treatment plant was applied to soils developed from limestone, marl and sandstone, showing contrasting alkalinity and texture. The compounds analysed were: linear alkylbenzene sulphonates (LAS) with a 10-13 carbon alkylic chain, and nonylphenolic compounds, including nonylphenol (NP) and nonylphenol ethoxylates with one and two ethoxy groups (NP1EO+NP2EO). These compounds were studied because they frequently exceed the limits proposed for sludge application to land in Europe. After nine months, LAS decomposition was 86-96%, and NP+NP1EO+NP2EO decomposition was 61-84%, which can be considered high. Temporal trends in LAS and NP+NP1EO+NP2EO decomposition were similar, and the concentrations of both types of compounds were highly correlated. The decomposition rates were higher in the period of 6-9 months (summer period) than in the period 0-6 months (winter+spring period) for total LAS and NP+NP1EO+NP2EO. Differences in decay rates with regard to soil type were not significant. The average values of decay rates found are similar to those observed in agricultural soils.


Factors influencing bone lead concentration in a suburban community assessed by noninvasive K x-ray fluorescence.
To determine the influence of demographic, exposure and medical factors on the bone lead concentration of subjects with background (nonindustrial) environmental lead exposure. Survey. Suburban residential community. A total of 101 subjects (49 males, 52 females; aged 11 to 78 years) were recruited from 49 of 123 households geographically located in a suburban residential neighborhood unexposed to any major source of industrial lead emissions. Cortical bone lead concentrations in the midshaft of the tibia were noninvasively measured by in vivo K x-ray fluorescence. Blood lead concentrations were measured by anodic stripping voltammetry. An administered questionnaire assessed potential sources of lead exposure and medical conditions affecting bone metabolism. After the exclusion of one outlier, log-transformed bone lead concentration was highly correlated with age (r = .71; P < or = .0001). Bone lead concentration showed no significant change up to age 20 years, increased with the same slope in men and women between ages 20 and 55 years, and then increased at a faster rate in men older than 55 years. In addition to the variables age and sex, the best fitting multiple regression model for bone lead concentration (R2 = .66; P < or = .0001) revealed a positive correlation with total pack-years of cigarette smoking and a negative correlation with a history of having nursed an infant for longer than 2 weeks. Blood lead concentrations of the subjects were low (geometric mean, 0.24 mumol/L [4.9 micrograms/dL]) and after log transformation were weakly correlated with log-transformed bone lead concentration (r = .23; P = .02). The age- and sex-related increases in bone lead concentration found by K x-ray fluorescence concur with published postmortem studies of bone lead concentration and are consistent with the kinetics of bone turnover and secular trends in lead exposure. These data help to establish a reference range for assessing the lead burden of other populations with environmental or occupational lead exposure.


Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering.
Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output neurons of the retina. Glaucoma is the most common cause of irreversible blindness and affects ∼80 million people worldwide with many more undiagnosed. The major risk factors for glaucoma are genetics, age, and elevated intraocular pressure. Current strategies only target intraocular pressure management and do not directly target the neurodegenerative processes occurring at the level of the retinal ganglion cell. Despite strategies to manage intraocular pressure, as many as 40% of glaucoma patients progress to blindness in at least one eye during their lifetime. As such, neuroprotective strategies that target the retinal ganglion cell and these neurodegenerative processes directly are of great therapeutic need. This review will cover the recent advances from basic biology to on-going clinical trials for neuroprotection in glaucoma covering degenerative mechanisms, metabolism, insulin signaling, mTOR, axon transport, apoptosis, autophagy, and neuroinflammation. With an increased understanding of both the basic and clinical mechanisms of the disease, we are closer than ever to a neuroprotective strategy for glaucoma.


Non-targeted metabolomics of quinoa seed filling period based on liquid chromatography-mass spectrometry.
Quinoa (Chenopodium quinoa Willd.), an herb belonging to the amaranth family, is rich in minerals, amino acids, vitamins, proteins, and flavonoids. Its grain, compared with other major grains, has unique nutritional value with tremendous applications. This study used four independently bred high-generation lines (seed colors) of quinoa as materials to further understand the metabolic differences in the filling periods of quinoa varieties. Additionally, the non-targeted metabolome of quinoa seeds 35 and 42 days after flowering, respectively, were studied via liquid chromatography-mass spectrometry. The two filling periods of yellow, white, black, and red quinoa grains resulted in significant differences in the metabolites, particularly in L-methionine, S-adenosyl-L-homocysteine, S-adenosyl-L-methionine, pyruvate, fumarate, and oxaloacetate. Soluble sugar, amino acid, and fatty acid contents in quinoa increased after 42 days of flowering. There were metabolic differences between the sugar phosphates (L-fucose, D-mannose-6-phosphate, xylulose-5-phosphate, sedoheptulose-7-phosphate), amino acid (alanine), and organic compounds (kynurenate, tryptamine, serotonin, bilirubin) among the four quinoa varieties. The relative difference in the metabolites was largest when the yellow quinoa grain was compared with the other quinoa varieties and smallest when the red and black varieties were compare. The results of this study provide a basis for the reproduction and identification of new quinoa varieties, as well as for screening potential quality control target genes by combining genomics and transcriptomics.


A Matter of Size and Placement: Varying the Patch Size of Anisotropic Patchy Colloids.
Non-spherical colloids provided with well-defined bonding sites-often referred to as patches-are increasingly attracting the attention of materials scientists due to their ability to spontaneously assemble into tunable surface structures. The emergence of two-dimensional patterns with well-defined architectures is often controlled by the properties of the self-assembling building blocks, which can be either colloidal particles at the nano- and micro-scale or even molecules and macromolecules. In particular, the interplay between the particle shape and the patch topology gives rise to a plethora of tilings, from close-packed to porous monolayers with pores of tunable shapes and sizes. The control over the resulting surface structures is provided by the directionality of the bonding mechanism, which mostly relies on the selective nature of the patches. In the present contribution, we investigate the effect of the patch size on the assembly of a class of anisotropic patchy colloids-namely, rhombic platelets with four identical patches placed in different arrangements along the particle edges. Larger patches are expected to enhance the bond flexibility, while simultaneously reducing the bond selectivity as the single bond per patch condition-which would guarantee a straightforward mapping between local bonding arrangements and long-range pattern formation-is not always enforced. We find that the non-trivial interplay between the patch size and the patch position can either promote a parallel particle arrangement with respect to a non-parallel bonding scenario or give rise to a variety a bonded patterns, which destroy the order of the tilings. We rationalize the occurrence of these two different regimes in terms of single versus multiple bonds between pairs of particles and/or patches.


6-[(E)-2-Phenyl-vin-yl]-1H-indole.
The title compound, C(16)H(13)N, is essentially planar [maximum deviation from the least-squares plane = 0.081 (3) Å], with a dihedral angle of 1.65 (13)° between the planes of the indole and benzene rings. In the crystal, there are no significant inter-molecular π-π inter-actions [minimum ring centroid-centroid separation = 4.217 (5) Å].


Peripheral vascular trauma: a civilian experience.
A detailed review of 106 vascular injuries seen at the Mt. Sinai Hospital of Cleveland in a period of six-and-a-half years is presented. The type and location of the vascular injuries, the concomitant injuries, the preoperative evaluation, operative and post operative management, the complications and their management are discussed. The overall amputation rate in our cases was 4.7%, and for popliteal artery injuries 20%. The mortality rate was 5.6%.


[Diabetes and hypokinetic cardiopathy : when to consider mitochondrial disease?].
The association between diabetes mellitus and hypokinetic cardiomyopathy is frequent. We report a case of diabetes and hypokinetic cardiopathy in a 40-year-old man which led to the hypothesis of maternally inherited diabetes and deafness (MIDD) due to a mitochondrial disease. This diagnosis was confirmed by genetic testing which showed a DNA A3243G mutation in the mitochondria, the prevalence of which is 1-2% in diabetes mellitus. Cardiac abnormalities are frequent (18-34% of patients depending on the series) and the co-existence of left ventricular hypertrophy and systolic dysfunction is suggestive of this disease. Some authors have proposed co-enzyme Q as a treatment to improve the left ventricular ejection fraction and insulin secretion.


A Prospective Cohort Study on Accuracy of Dorsal Tangential Views to Avoid Screw Penetration With Volar Plating of Distal Radius Fractures.
To assess diagnostic performance of dorsal tangential views (DTVs) to detect dorsal screw protrusion in clinical practice. Prospective cohort study. Level-1 trauma center. Fifty consecutive patients undergoing volar plating for 50 distal radius fractures were prospectively included. Fluoroscopic DTVs were routinely obtained, and screw revision was documented. Multiplanar reconstructions of postoperative CTs allowed for detection and quantification of dorsal screw penetration using reproducible measuring techniques. Diagnostic performance (sensitivity, negative predictive value, positive predictive value, and accuracy) of DTV. Intraoperatively, in 16 of 50 patients (32%), screws were revised based on DTV, with 13 of 218 screws (6.0%) being revised due to dorsal prominence. One screw was changed because DTV showed it was in the distal radioulnar joint. Postoperatively, in 10 patients (20%), the computed tomography revealed 12 additional screws penetrating ≥1 mm with an average of 1.8 mm (range 1.0-4.5 mm). DTV had a sensitivity of 52%, a negative predictive value of 95%, and accuracy of 95%. No ≥1-mm protruding screw remained in the third compartment. In one-third of our patients, the incidence of protruding screws that can cause iatrogenic extensor tendon rupture was reduced by obtaining additional DTVs. Although DTV reduces the incidence of dorsal screw penetration considerably, this study reveals limited sensitivity. Therefore, one should keep in mind that dorsal screw penetration may go unnoticed on DTVs, and proper surgical technique remains paramount of DTV. Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Catalytic performance and reaction mechanisms of NO removal with NH3 at low and medium temperatures on Mn-W-Sb modified siderite catalysts.
Iron-based catalysts have been explored for selective catalytic reduction (SCR) of NO due to environmentally benign characters and good SCR activity. Mn-W-Sb modified siderite catalysts were prepared by impregnation method based on siderite ore, and SCR performance of the catalysts was investigated. The catalysts were analyzed by X-ray diffraction, H2-temperature-programmed reduction, Brunauer-Emmett-Teller, Thermogravimetry-derivative thermogravimetry and in-situ diffused reflectance infrared Fourier transform spectroscopy (DRIFTS). The modified siderite catalysts calcined at 450°C mainly consist of Fe2O3, and added Mn, W and Sb species are amorphous. 3Mn-5W-1.5Sb-siderite catalyst has a wide temperature window of 180-360°C and good N2 selectivity at low temperatures. In-situ DRIFTS results show NH4+, coordinated NH3, NH2, NO3- species (bidentate), NO2- species (nitro, nitro-nitrito, monodentate), and adsorbed NO2 can be discovered on the surface of Mn-W-Sb modified siderite catalysts, and doping of Mn will enhance adsorbed NO2 formation by synergistic catalysis with Fe3+. In addition, the addition of Sb can inhibit sulfates formation on the surface of the catalyst in the presence of SO2 and H2O. Time-dependent in-situ DRIFTS studies also indicate that both of Lewis and Brønsted acid sites play a role in SCR of NO by ammonia at low temperatures. The mechanism of NO removal on the 3Mn-5W-1.5Sb-siderite catalyst can be discovered as a combination of Eley-Rideal and Langmuir-Hinshelwood mechanisms with three reaction pathways. The mechanism of NO, oxidized by synergistic catalysis of Fe3+ and Mn4+/3+ to form NO2 among three pathways, reveals the reason of high NOx conversion of the catalyst at medium and low temperatures.