Three novel, multiple recombinant types of species of human mastadenovirus D (HAdV-D 73, 74 & 75) isolated from diarrhoeal faeces of immunocompromised patients.
Species D is the largest of the seven species of human mastadenoviruses (HAdV), but few of its multiple types are associated with asevere disease, e.g. epidemic keratoconjunctivitis. Many other types are hardly ever associated with significant diseases in immunocompetent patients, but have been isolated from the diarrhoeal faeces of terminal AIDS patients suggesting their role as opportunistic pathogens. Three novel HAdV-D strains were isolated from the faeces of three immunocompromised adult patients (clinical diagnoses: lymphoma, myelodysplastic syndrome and AIDS CDC3B, respectively). These strains were not typeable by imputed serology of the hexon and fibre gene and therefore complete genomic sequences were generated by next-generation sequencing (NGS). All three strains were multiple recombinants and fulfilled the criteria for designation as types 73, 74 and 75 with the penton/hexon/fibre genotype codes P67H45F27, P70H74F51 and P75H26F29, respectively. A novel genomic backbone and also a novel hexon neutralization epitope sequence were discovered in type 74, and a novel penton sequence in type 75. At the complete genome level, types 73, 74 and 75 were closely related neither to each other nor to type 70, which was previously isolated in the same region. However, these four HAdV-D types were closely related to each other in single genes and gene regions, e.g. penton, E1 and E4 due to recombination events in their phylogeny. In conclusion, regional co-circulation of opportunistic HAdV-D types facilitated co- and super-infections, which are essential for homologous recombination, and thus resulted in the evolution of novel genotypes by lateral gene transfer.


Fuzzy neural network approaches for robotic gait synthesis.
In this paper, a learning scheme using a fuzzy controller to generate walking gaits is developed. The learning scheme uses a fuzzy controller combined with a linearized inverse biped model. The controller provides the control signals at each control time instant. The algorithm used to train the controller is "backpropagation through time". The linearized inverse biped model provides the error signals for backpropagation through the controller at control time instants. Given prespecified constraints such as the step length, crossing clearance, and walking speed, the control scheme can generate the gait that satisfies these constraints. Simulation results are reported for a five-link biped robot.


18F alpha-methyl tyrosine PET studies in patients with brain tumors.
We have developed 18F-labeled alpha-methyl tyrosine (FMT) for PET imaging. The aim of this study was to evaluate the clinical application potential of FMT for patients with brain tumors. Eleven healthy volunteers and 20 patients with brain tumors were injected with 185 MBq (5 mCi) FMT. In 3 healthy volunteers, whole-body imaging and urinary and plasma analysis were conducted for the assessment of the biodistribution of FMT. The normal range of cortical standardized uptake value (SUV) as a reference for comparing tumor SUV of FMT was estimated by using PET data obtained at 30 min postinjection in 8 healthy volunteers. Dynamic PET scans were conducted for 100 min in 4 healthy volunteers and for 30 min in 15 patients with brain tumors. The 10-min static images in another 4 volunteers and all patients were obtained at 30 min postinjection. In 13 patients, FMT uptake in the brain tumor was compared with 18F-fluorodeoxyglucose (FDG). Tumor-to-normal cortex count (T/N) ratio and tumor-to-white matter count (T/W) ratio and SUVs of brain tumors were determined on FMT and FDG PET images. Approximately 1480 MBq (40 mCi) FMT were produced in one radiosynthesis. Percentage injected dose (%ID) of FMT in the brain ranged from 2.8% to 4.9%, and approximately 50%ID of FMT was excreted in urine during 60 min postinjection, of which 86.6% was unmetabolized FMT. A faint physiological brain uptake with SUV of 1.61 +/- 0.32 (mean +/- SD, n = 8) was observed in healthy volunteers. Tumor SUV of FMT ranged from 1.2 to 8.2, with mean value of 2.83 +/- 1.57 (n = 23), which was significantly higher than that of the cortical area in healthy volunteers (P < 0.01). T/N and T/W ratios of FMT were significantly higher than those of FDG (2.53 +/- 1.31 versus 1.32 +/- 1.46, P < 0.001; 3.99 +/- 2.10 versus 1.39 +/- 0.65, P < 0.0001, respectively). FMT, like other radiolabeled amino acids, can provide high-contrast PET images of brain tumors.


Femoroacetabular Impingement: What the Surgeon Wants to Know.
Femoroacetabular impingement (FAI) is increasingly recognized as a risk factor for early hip degeneration in young active patients. The diagnosis depends on clinical examination and proper imaging that should be able to identify abnormal and sometimes subtle morphological changes. Labral tears and cartilage lesions rarely occur without underlying bone abnormalities. Surgical approaches to treat FAI are increasing significantly worldwide, even without a clearly defined consensus of what should be accepted as the standard imaging diagnosis for FAI morphology.Hip abnormalities encompass many variations related to the shape, size, and spatial orientation of both sides of the joint and can be difficult to characterize if adequate imaging is not available.This article presents a comprehensive review about the information orthopaedic surgeons need to know from radiologists to plan the most rational approach to a painful hip resulting from a mechanical abnormality.


Relationship Between 18F-fluorodeoxyglucose Uptake on Positron Emission Tomography and Aortic Calcification.
Introduction: Although 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been widely utilized to assess the extent of inflammation, the association between the extent and severity of atherosclerosis and 18F-FDG uptake on PET remains unexamined. The current study aimed to investigate whether aortic calcium (AC) scores were associated with increased aortic uptake of 18F-FDG on PET. Methods: A total of 167 consecutive patients with suspected lung cancer but unproven malignancy who underwent non-contrast-enhanced computed tomography (CT) and 18F-FDG PET/CT were enrolled. The average standardized uptake values in the ascending aorta were used to calculate the target-to-background ratio (Mean TBR). The total (thoracic and abdominal) AC scores were measured on non-contrast-enhanced chest and abdominal CT using the Agatston method, and were categorized into three groups (0, 1-399, and ≥400). The relationship between total AC scores and 18F-FDG uptake in the ascending aorta was assessed using multivariate linear regression analysis. Results: In total, 68.26% were male, and a mean age was 67.10±14.70 years. Mean TBR values increased progressively with total AC score 0, 1-399, and ≥400 (1.01±0.07, 1.08±0.09, and 1.11±0.11, respectively; p<0.00001). Multivariate linear regression analysis revealed that increased total AC scores of 1-399 (β=0.06, 95% CI: 0.01-0.11, p=0.02) and ≥400 (β=0.11, 95% CI: 0.06-0.16, p<0.001) were significantly associated with higher Mean TBR. Conclusions: The current study demonstrated that total AC scores were associated with Mean TBR. Patients with a greater extent and severity of aortic calcifications may possess increased atherosclerotic inflammatory activity as measured by 18F-FDG PET/CT.


Starch Characteristics Linked to Gluten-Free Products.
The increasing prevalence of coeliac disease (CD) and gluten-related disorders has led to increasing consumer demand for gluten-free products with quality characteristics similar to wheat bread. The replacement of gluten in cereal-based products remains a challenge for scientists, due to its unique role in network formation, which entraps air bubbles. When gluten is removed from a flour, starch is the main component left. Starch is used as gelling, thickening, adhesion, moisture-retention, stabilizing, film forming, texturizing and anti-staling ingredient. The extent of these properties varies depending on the starch source. The starches can additionally be modified increasing or decreasing certain properties of the starch, depending on the application. Starch plays an important role in the formulation of bakery products and has an even more important role in gluten-free products. In gluten-free products, starch is incorporated into the food formulation to improve baking characteristics such as the specific volume, colour and crumb structure and texture. This review covers a number of topics relating to starch; including; an overview of common and lesser researched starches; chemical composition; morphology; digestibility; functionality and methods of modification. The emphasis of this review is on starch and its properties with respect to the quality of gluten-free products.


[Experimental study on the relationship between neuropeptide substance P and wound healing in scalded rats].
To explore the relationship between neuropeptide substance P (SP) and wound healing in scalded rats. (1) Scalded rats with different degrees of scald injury were employed as the experimental model and were sacrificed at 24 post scald hour (PSH), and on 3, 7 and 14 post scald days (PSD). The SP content in the wound was detected with radioimmunoassay method. (2) The murine granulation tissue fibroblasts (GTF) were cultured with different culture media, and divided into control, SP and Spantide (SP receptor antagonism) groups. The effects of SP and Spantide on the cellular activity and apoptotic rate of murine GTF were assessed in vitro. There was significant difference of the SP content among the superficial (145 +/- 78) ng/g, partial (94 +/- 48 ng/g) and full thickness (53 +/- 27 ng/g) scald wounds at 24 PSH (P < 0.01), while the SP content in partial thickness burn wound on 3 and 7 PSD obviously increased; and that in deep partial thickness burn wound obviously increased on 7 and 14 PSD. But the SP content remained unchanged in full thickness scald wound. (2) SP could promote the activity of GTF and inhibit its apoptosis (The GTF activity in control, SP groups were 0.21 +/- 0.05, 0.36 +/- 0.07, respectively, P < 0.01). Spantide could inhibit the interaction between SP and GTF. SP can promote GTF proliferation, and the SP content in wound is closely associated with the depth of the injury and wound healing capacity.


[Development of 2,4,6-trinitrophenol examination methods to evaluate the features of its distribution in warm-blooded animals].
Is to study a 2, 4, 6-trinitrophenol (2.4,6-TNP) distribution in warm-blooded animals using physical chemical analysis methods after intragastric injection of toxicant. The methods of thin-layer chromatography, spectrophotometry and high-efficient liquid chromatography were used in the study process. Four-months-old rats of the Wistar line (males) were considered as a model of warm-blooded organisms. The investigated substance in amount of three-times LD50 was intragastrically injected in the aqueous-suspension state. 2.4,6-TNP was isolated by a mixture of acetone-acetonitrile (1:1) in a double (by 0.5 of hour) infusing mode from the bioactive matrix of experimental animals, sustaining the mass ratio of isolated agent to bioactive matrix equaled to 2:1. Purification and preliminary identification of analyte were conducted on «Sorbfil» plates (mobile phase - acetone - chloroform (7:3)), confirming identification - by absorption in dimethylformamide medium and by retention time in column (64×2 mm) of «Separon C-18» sorbent during elution by acetonitrile-water (2:8) mixture. The evaluation of 2, 4, 6-trinitrophenol quantitative content by optical density of dimethylformamide solution of analyte at 379 nm was carried out. The analyte in unchanged form was found in blood, parenchymatous and hollow organs, their contents and blood of experimental animals. The highest content of 2.4,6-TNP (mg/100 gr) was revealed in gastric content (149.88±22.70), gastric tissue (97.89±4.86), blood (15.91±0.90) and muscles (10.87±1.91).


The sheep KAP8-2 gene, a new KAP8 family member that is absent in humans.
The keratin-associated proteins (KAPs) are fundamental components of hair and wool fibres, and are believed to in part be responsible for some of the properties of these fibres. KAPs can be divided into three groups: the high sulphur (HS) KAPs, the ultra-high sulphur (UHS) KAPs and the high glycine-tyrosine (HGT) KAPs. KAP8 is a HGT-KAP family and was believed to be coded for by a single gene in both humans and sheep. However, the recent identification of a KAP8-2 gene in goats led us to investigate whether a KAP8-2 gene exists in sheep. A BLAST search of the Ovine Genome Assembly v2.0 using the coding sequence of caprine KRTAP8-2 identified a homologous region on sheep chromosome 1 (OAR1:123005473_123005664; E = e(-101)). This region was clustered with a number of previously identified KAP genes including (in order from the centromere) KRTAP11-1, KRTAP7-1, KRTAP8-1, KRTAP6-2, KRTAP6-1, KRTAP13-3 and KRTAP24-1. PCR-SSCP analysis of the notional gene revealed two dissimilar PCR-SSCP banding patterns, representing two DNA sequences. A single nucleotide difference 21 bp upstream of the TATA box was identified. The two sequences did not have great homology with known ovine KRTAP sequences, but high sequence identity was found with KRTAP8-2 from goats and reindeer. These results suggest that sheep possess a KAP8-2 gene and that this gene is polymorphic. The notional KAP8-2 protein is comprised of 63 amino acid residues and is rich in glycine and tyrosine, but has a low cysteine content. In contrast to other HGT-KAPs, ovine KAP8-2 contains more acidic amino acid residues, and this would likely result in a lower isoelectric point (pI) of 6.3.


The role of physical barriers in the location of avian suture zones in the Guiana Shield, northern Amazonia.
Suture zones represent natural forums in which to examine the role of geography and ecology in the speciation process. Here, we conduct a comparative analysis designed to investigate the location of avian phylogeographic breaks and contact zones in the Guiana Shield, northern Amazonia. We use distributional and genetic data from 78 pairs of avian taxa to address whether phylogeographic breaks and contact zones are associated with contemporary landscape features. Using spatially explicit statistical models, we found that phylogeographic breaks and contact zones are not randomly distributed throughout the landscape. In general, geographic breaks cluster along physical barriers (rivers, nonforested habitats, and small mountain ranges), whereas contact zones aggregate where these barriers either break down or are easier to overcome, such as around rivers' headwaters. Our results indicate that although major Amazonian rivers are often key determinants of taxon boundaries, the "riverine barrier effect" is a synergistic consequence of the wide lower reaches of some rivers, coupled with nonriverine landscape features at the headwaters. Our data suggest that ancestral refugia are not necessary to explain current distribution patterns and that pairs of codistributed taxa do not seem to be the result of simultaneous diversification processes.


Case report: Squamous cell carcinoma of the prostate-a clinicopathological and genomic sequencing-based investigation.
Squamous differentiation of prostate cancer, which accounts for less than 1% of all cases, is typically associated with androgen deprivation treatment (ADT) or radiotherapy. This entity is aggressive and exhibits poor prognosis due to limited response to traditional treatment. However, the underlying molecular mechanisms and etiology are not fully understood. Previous findings suggest that squamous cell differentiation may potentially arise from prostate adenocarcinoma (AC), but further validation is required to confirm this hypothesis. This paper presents a case of advanced prostate cancer with a combined histologic pattern, including keratinizing SCC and AC. The study utilized whole-exome sequencing (WES) data to analyze both subtypes and identified a significant overlap in driver gene mutations between them. This suggests that the two components shared a common origin of clones. These findings emphasize the importance of personalized clinical management for prostate SCC, and specific molecular findings can help optimize treatment strategies.


A Combined Intervention of Single Vision Plus Lens and Tropicamide in the Treatment of Pseudomyopia: A Perspective Case Report from Nepal.
This study highlights the role of cycloplegic refraction in the detection of accommodative spasm and the use of tropicamide 1% as cycloplegic and single vision plus lens for its management. This was a case study carried at tertiary eye hospital in Kathmandu, Nepal. In this study, 2 subjects presenting with complain of sudden onset of diminution of vision for near and distance along with asthenopic symptoms having history of prolonged near work were recruited. Pre-cycloplegic refraction showed fluctuating myopic refractive error which after cycloplegia showed a significant hyperopic shift. Single vision plus lens (base on post-mydriatic treatment) giving optimal vision for near and distance along with tropicamide 1% twice a day basis and abstinence of triggering factor was started as initial treatment modality. Subjects were kept under close surveillance and followed up fortnightly over 2 months. During this period, the dosages of tropicamide were gradually tapered based on symptomatic relief of patient and no recurrence of the condition was observed in both subjects for next 2 month.


Arabidopsis thaliana NADP-malic enzyme isoforms: high degree of identity but clearly distinct properties.
The Arabidopsis thaliana genome contains four NADP-malic enzymes genes (NADP-ME1-4). NADP-ME4 is localized to plastids whereas the other isoforms are cytosolic. NADP-ME2 and 4 are constitutively expressed, while NADP-ME1 is restricted to secondary roots and NADP-ME3 to trichomes and pollen. Although the four isoforms share remarkably high degree of identity (75-90%), recombinant NADP-ME1 through 4 show distinct kinetic properties, both in the forward (malate oxidative decarboxylation) and reverse (pyruvate reductive carboxylation) reactions. The four isoforms behave differently in terms of reversibility, with NADP-ME2 presenting the highest reverse catalytic efficiency. When analyzing the activity of each isoform in the presence of metabolic effectors, NADP-ME2 was the most highly regulated isoform, especially in its activation by certain effectors. Several metabolites modulate both the forward and reverse reactions, exhibiting dual effects in some cases. Therefore, pyruvate reductive carboxylation may be relevant in vivo, especially in some cellular compartments and conditions. In order to identify residues or segments of the NADP-ME primary structure that could be involved in the differences among the isoforms, NADP-ME2 mutants and deletions were analysed. The results obtained show that Arg115 is involved in fumarate activation, while the amino-terminal part is critical for aspartate and CoA activation, as well as for the reverse reaction. As a whole, these studies show that minimal changes in the primary structure are responsible for the different kinetic behaviour of each AtNADP-ME isoform. In this way, the co-expression of some isoforms in the same cellular compartment would not imply redundancy but represents specificity of function.


Conjugate eye movements and gamma power modulation of the EEG in persistent vegetative state.
Power in the gamma band EEG increases during saccades in normal subjects. To develop a potential method to quantify signs of cortical responsiveness in persistent vegetative state (PVS) we quantified gamma range EEG in association with conjugate slow ballistic eye movements (SBEM). The EEG and the simultaneous electro-oculogram were recorded in 14 (8F/6M) PVS patients. Clinical scoring was based on the Glasgow Coma Scale (GCS) and Coma Rating Scale (CRS). The Wavelet Transform, followed by Hilbert transform was applied to the EEG and gamma power distribution was quantified relative to the timing of an eye movement. We correlated the clinical and the neurophysiological measures. Gamma activity was present in all PVS patients. Its power was modulated in association with eye movements only in less severely affected patients, with minimum power prior to, and maximum power during the eye movement. In severely affected patients there was no evidence of a temporal relationship between gamma power and the phase of the eye movement. Detecting changes in the time course of gamma power in relation to conjugate ballistic eye movements provides a quantitative neurophysiological method for prospective longitudinal studies to explore if the preservation of this CNS function relates to the potential for recovery in PVS patients.


Intra-abdominal desmoplastic small round cell tumor.
Intra-abdominal desmoplastic small round cell tumor (IDSRCT) is a unique, highly aggressive neoplasm that chiefly affects male adolescents and young adults and most frequently presents as a large abdominal mass with widespread peritoneal involvement at the time of diagnosis. We present two cases of IDSRCT in a young male and a female. Both typically presented with diffuse peritoneal involvement.


Optical interband transitions in relaxor-based ferroelectric 0.93Pb(Zn(13)Nb(23))O(3)-0.07PbTiO(3) single crystal.
The optical transmission spectrum of [111](c) poled relaxor-based ferroelectric single crystal 0.93Pb(Zn(13)Nb(23))O(3)-0.07PbTiO(3) (PZN-0.07PT) was measured in the range of ultraviolet to near infrared. The optical absorption edge has been determined and the wavelength dependence of the absorption coefficient was calculated. The direct energy gap E(gd)=3.144 eV, indirect energy gap E(gi)=2.915 eV, and phonon energy E(p)=0.097 eV (or 782 cm(-1)) were determined based on the theory of band to band transitions. It was also confirmed by Raman spectra that the indirect transition for the [111](c) poled PZN-0.07PT single crystal is mainly due to the contribution of 780 cm(-1) phonon corresponding to the Nb-O-Zn bond stretching mode.


[Comparative investigation of the non-histone proteins of chromatin from pigeon erythroblasts and erythrocytes].
Chromosomal non-histone proteins are obtained from nuclei of two types of pigeon erythroid cells: erythroblasts (cells active in RNA synthesis) and erythrocytes (cells with repressed RNA synthesis). They are well soluble in solutions of low ionic strength. Electrophoretic separation of the obtained non-histone proteins in polyacrylamide gels with urea and SDS shows the presence of qualitative differences in the pattern of non-histone proteins of chromatine from erythroblasts and erythrocytes. By electrophoresis in urea some protein bands of non-histone proteins of chromatine from erythroblasts were found which disappear with the aging of cells. At the same time two protein fractions were observed in chromatine from erythrocytes which were absent in that of erythroblasts. Disappearance of some high molecular weight protein fractions from erythrocyte chromatine as compared to erythroblasts was observed by separation of the non-histone proteins in the presence of SDS. These fractions of the non-histone proteins disappearing during aging of cells are well extractable from erythroblast chromatine by 0.35 M NaCl solution. In the in vitro system with E. coli RNA polymerase addition of non-histone proteins of chromatine from erythroblasts to chromatine from erythrocytes increases RNA synthesis 2--3 times. At the same time addition of non-histone proteins from erythrocytes is either without any influence on this process or somewhat inhibiting.


Spine loading during asymmetric lifting using one versus two hands.
This study documented three-dimensional spinal loading associated with asymmetric lifting while using either one or two hands to perform the task. Lift asymmetry was defined as a function of the load origin relative to the sagittal plane of the body. Lifts occurred at 0, 30, or 60 degrees off the sagittal plane on both sides of the body (lifting from the right and from the left relative to the sagittal plane). Ten subjects lifted a 13.7 kg box from one of these origins to a sagittally symmetric destination. Spinal loads were estimated through the use of a validated EMG-assisted model. Spine compression and lateral shear forces increased as the lift origin became more asymmetric. However, spinal compression and lateral shear increased by about twice the rate when lifting from origins to the left of the sagittal plane compared to lifting from origins to the right of the sagittal plane. Anterior-posterior spinal shear decreased as asymmetry increased with larger decreases occurring when lift origins occurred to the right of the sagittal plane. One-hand lifting changed the compression and shear profiles significantly. One-hand lifts using the hand on the same side of the body as the load resulted in compression forces that were approximately equal to those observed when lifting with two hands in a sagittally symmetric position. Anterior-posterior shear decreased and lateral shear increased under these conditions. These results reflect the trade-offs that must be considered among spinal forces during asymmetric lifting while using one or two hands. These findings have significant implications for task assessment interpretation and workplace design.


Increased Risk of Metabolic Syndrome in Antidepressants Users: A Mini Review.
Mounting evidence has shown that the risk of metabolic syndrome (MetS) is substantially overlapping in the diagnostic subgroups of psychiatric disorders. While it is widely acknowledged that patients receiving antipsychotic medications are at higher risk of MetS than antipsychotic-naive ones, the association between antidepressants and MetS is still debated. The goal of our mini review was to analyse the relationship among depressive symptoms, antidepressant use and the occurrence of MetS. Adhering to PRISMA guidelines, we searched MEDLINE, reference lists and journals, using the following search string: ((("Mental Disorders"[Mesh]) AND "Metabolic Syndrome"[Mesh]) AND "Antidepressive Agents"[Mesh]), and retrieved 36 records. Two reviewers independently assessed records and the mini review eventually included the data extracted from 8 studies. The Newcastle-Ottawa Scale was used to assess the quality of the selected studies. Overall, the results of the mini review seem to support the association among depressive symptoms, antidepressants therapy and MetS. Except for H1-R high-affinity ones, the relationship between antidepressants and MetS still needs to be clarified. Considering the widespread prescription of antidepressants, both on behalf of psychiatrists and primary care physicians, further research on this topic is recommended.


Odourant dominance in olfactory mixture processing: what makes a strong odourant?
The question of how animals process stimulus mixtures remains controversial as opposing views propose that mixtures are processed analytically, as the sum of their elements, or holistically, as unique entities different from their elements. Overshadowing is a widespread phenomenon that can help decide between these alternatives. In overshadowing, an individual trained with a binary mixture learns one element better at the expense of the other. Although element salience (learning success) has been suggested as a main explanation for overshadowing, the mechanisms underlying this phenomenon remain unclear. We studied olfactory overshadowing in honeybees to uncover the mechanisms underlying olfactory-mixture processing. We provide, to our knowledge, the most comprehensive dataset on overshadowing to date based on 90 experimental groups involving more than 2700 bees trained either with six odourants or with their resulting 15 binary mixtures. We found that bees process olfactory mixtures analytically and that salience alone cannot predict overshadowing. After normalizing learning success, we found that an unexpected feature, the generalization profile of an odourant, was determinant for overshadowing. Odourants that induced less generalization enhanced their distinctiveness and became dominant in the mixture. Our study thus uncovers features that determine odourant dominance within olfactory mixtures and allows the referring of this phenomenon to differences in neural activity both at the receptor and the central level in the insect nervous system.


Effect of xylanase on the performance of laying hens fed a low energy corn and soybean diet.
This study was conducted to determine the effect of high- and low-activity xylanase in a corn and soybean diet on the performance of laying hens. There were 2 phases each with 4 treatment diets: positive control (PC), negative control (NC) with lower metabolizable energy (ME) and nutrient density, and 2 different xylanases supplemented to the NC diet. Phase 1 was 23-43 wk of age and phase 2 was 43-58 wk, for a total duration of 35 wk. The NC diet had a lower ME in phase 2 than phase 1. There were 72 cages with 3 Bovan White Leghorns each. Egg production (EP) was recorded daily, feed intake (FI) weekly, and average egg weights (EW) biweekly. Egg production and FI were calculated using biweekly periods, also used to determine egg mass (EM) and feed conversion (FC) with biweekly EW. BW was recorded and analyzed for weeks 0, 10, 20, and 35 of the study. Egg production did not differ among treatment groups (phase 1: P = 0.47; phase 2: P = 0.54). In phase 1, EW and EM were significantly lower in the NC diet with enzyme B, compared to both the PC and NC diets (P = 0.019; P = 0.01). The PC diet yielded higher EW than all other treatments in phase 2 (P = 0.036), but no differences in EM were present (P = 0.12). Baseline BW was not different (P = 0.63), but hens fed the PC diet had higher BW in subsequent measurements (P ≤ 0.05). Hens fed the PC diet had lower FI than all other treatment groups in both phases (P = 0.0001), and had an improved FC than the 2 enzyme groups in phase 1 (P = 0.0001) and all other treatment groups in phase 2 (P = 0.0001). The enzymes did not improve the performance of the birds.


Autophagy in fibroblasts induced by cigarette smoke extract promotes invasion in lung cancer cells.
We investigated the effects of cigarette smoke extract (CSE) on lung fibroblasts and found that the invasiveness of lung cancer cells was facilitated by the conditioned medium from CSE-treated fibroblasts. CSE induced autophagy in fibroblasts and increased the expression of autophagy-related proteins, including optineurin and Ras-related protein Rab1B. Afterward, the fibroblasts produced high levels of interleukin-8 (IL-8), which promoted cancer cell invasion. The inhibition of either optineurin or Rab1B abrogated a rise in microtubule-associated protein 1 light chain 3 β and a decrease in p62 protein, as well as the production of IL-8, in CSE-treated fibroblasts. A three-dimensional invasion assay using cancer cell spheroids revealed that the invasion of cancer cells alone and the fibroblast-led cancer cell invasion were both enhanced by the conditioned media from CSE-treated fibroblasts. These results suggest that cigarette smoke may induce autophagy and IL-8 secretion in lung fibroblasts and modify the microenvironment to favor invasion of lung cancer cells.


Role of C1QBP/p32 and its Therapeutic Potential in Breast Carcinoma and other Cancers.
The complement component 1, q subcomponent binding protein (C1QBP/gC1q-R/p32/HABP1/TAP/YBAP1), is a ubiquitous, multifunctional protein. C1QBP localizes mainly to mitochondria due to its N-terminal mitochondrial localization signal, but it can also be found in different subcellular compartments including the cell surface, nucleus, cytoplasm, and extracellular space. C1QBP has been reported to interact with a variety of proteins that have apparently unrelated functions. C1QBP has also been observed to interact with hyaluronic acid and RNA. These findings suggest that C1QBP has both mitochondrial and extramitochondrial functions. The C1QBP binding sites of many partner proteins are located within basic and intrinsically disordered regions of these molecules, consistent with the hypothesis that C1QBP functions as a molecular chaperone. C1QBP expression is elevated in various types of human cancers, including breast cancer. Moreover, it has been implicated in the development, progression, and metastasis of cancer cells based on loss-of-function and gain-of-function studies using cancer cell lines and xenograft models. Hence C1QBP could be a molecular target in breast cancer therapy. Studies using antibodies, tumor homing peptides such as LyP-1, and small molecules that target C1QBP warrant further investigation as C1QBP is a potential therapeutic target.


Outcomes and informatics.
To provide an overview of the potential contribution that informatics can make for pathologists who become involved in outcomes assessment and management. Contemporary scientific articles centered on pathologists and the assessment of outcomes, the definitions of outcomes assessment and management, and related methodologic issues, especially those pertaining to information technology and outcomes, and a summary of eight independent group process sessions involving volunteer pathologists and a group facilitator discussing issues related to informatics and outcomes as structured by a clinical scenario with focusing questions. Articles reviewed were drawn primarily from the literature published since 1985 and found through Medline key word searches of titles and abstracts; likely articles were then selected for subsequent detailed review on the basis of the abstract's contents. Group process data were drawn from summaries of each of the eight groups as prepared by the facilitator from notes taken during the session by a designated scribe. It is crucial for pathologists to participate in clinical outcomes studies. Informatics can serve as a tool kit for performing outcomes studies relevant to pathology (eg, collect data or analyze data), or it can be seen as a malleable component of health care processes that can be modified to achieve improved outcomes. Pathologists see many potential avenues for using informatics to leverage the impact that the pathologist and laboratory can have on clinical outcomes. Focusing on some specific informatics learning objectives can help the pathologist become a leader in outcomes studies.


Effects of beer and hop on ionotropic gamma-aminobutyric acid receptors.
Beer induced the response of the ionotropic gamma-aminobutyric acid receptors (GABA(A) receptors) expressed in Xenopus oocytes, indicating the presence of gamma-aminobutyric acid (GABA)-like activity. Furthermore, the pentane extract of the beer, hop (Humulus lupulus L.) oil, and myrcenol potentiated the GABA(A) receptor response elicited by GABA. The GABA(A) receptor responses were also potentiated by the addition of aliphatic esters, most of which are reported to be present in beer flavor. Aliphatic esters showed the tendency to decrease in the potentiation of the GABA(A) receptor response with an increase in their carbon chain length. When myrcenol was injected to mice prior to intraperitoneal administration of pentobarbital, the pentobarbital-induced sleeping time of mice increased additionally. Therefore, the beer contained not only GABA-like activity but also the modulator(s) of the GABA(A) receptor response.


Skeletal muscle disease in rheumatoid arthritis: the center of cardiometabolic comorbidities?
Despite its critical roles in body movement, structure, and metabolism, skeletal muscle remains underappreciated in the context of rheumatoid arthritis. In rheumatoid arthritis, chronic inflammation, physical inactivity, and medication toxicities impair skeletal muscle. These skeletal muscle alterations contribute to continued rheumatoid arthritis disparities in physical function and cardiometabolic health. In the prebiologic disease-modifying antirheumatic drug era, rheumatoid arthritis skeletal muscle atrophy was the central feature of 'rheumatoid cachexia,' a hypermetabolic state driven by chronic systemic inflammation and muscle protein degradation. In the current era, rheumatoid arthritis muscle deficits are less visible, yet persist as a key component of 'sarcopenic obesity.' In rheumatoid arthritis sarcopenic obesity, chronic inflammation, physical inactivity, and medication toxicities contribute to muscle contractile deficits, inflammation, altered metabolism, and intramuscular adiposity, a key predictor of rheumatoid arthritis disability and insulin resistance. Rheumatoid arthritis skeletal muscle disease in the current era is defined by impaired contractile function (poor strength and endurance) and sarcopenic obesity (decreased muscle mass, increased fat mass, and intramuscular adiposity). These muscle impairments contribute to disability and cardiometabolic disease in rheumatoid arthritis. Management should focus on monitoring of rheumatoid arthritis muscle function and body composition, limiting potentially myotoxic drugs, and prescription of exercise training.


Function of PsbO, the photosystem II manganese-stabilizing protein: probing the role of aspartic acid 157.
The D157N, D157E, and D157K mutations in the psbO gene encoding the photosystem II (PSII) manganese-stabilizing protein from spinach, exhibit near-wild-type PSII binding but are significantly impaired in O(2) evolution activity and Cl(-) retention by PSII [Popelkova et al. (2009) Biochemistry 48, 11920-11928]. To better characterize the role of PsbO-Asp157 in eukaryotic PSII, the effect of mutations in Asp157 on heat-induced changes in PsbO solution structure, O(2) release kinetics, and PSII redox reactions both within and outside the oxygen-evolving complex (OEC) have been examined. The data presented here show that Asn, Glu, or Lys mutations in PsbO-Asp157 modify PsbO thermostability in solution, which is consistent with the previously reported perturbation of the functional assembly of PsbO-Asp157 mutants into PSII that caused inefficient Cl(-) retention by PSII. Fluorescence decay signals from PSII reconstituted with Asp157 mutants indicate that that the Q(A)(-) to Q(B) transition on the PSII reducing side is unaffected, but complex alterations are detected on the PSII oxidizing side that affect the recombination of Q(A)(-) with the O(2)-evolving complex. In addition, oxygen yield on the first flash is increased, which indicates an impaired ability of mutant-reconstituted PSII samples to decay back to the S(1) state in the dark.


Ferrofluid-Based Droplet Interface Bilayer Networks.
Droplet interface bilayer (DIB) networks allow for the construction of stimuli-responsive, membrane-based materials. Traditionally used for studying cellular transport phenomena, the DIB technique has proven its practicality when creating structured droplet networks. These structures consist of aqueous compartments capable of exchanging their contents across membranous barriers in a regulated fashion via embedded biomolecules, thus approximating the activity of natural cellular systems. However, lipid bilayer networks are often static and incapable of any reconfiguration in their architecture. In this study, we investigate the incorporation of a magnetic fluid or ferrofluid within the droplet phases for the creation of magnetically responsive DIB arrays. The impact of adding ferrofluid to the aqueous phases of the DIB networks is assessed by examining the bilayers' interfacial tensions, thickness, and channel activity. Once compatibility is established, potential applications of the ferrofluid-enabled DIBs are showcased by remotely modifying membrane qualities through magnetic fields. Ferrofluids do not significantly alter the bilayers' properties or functionality and can therefore be safely embedded within the DIB platform, allowing for remote manipulation of the interfacial bilayer properties.


Cervical cancer prevention for all the world's women: genuine promise resides in skilled quality management rather than novel screening approaches.
The debate over the best route for cervical cancer prevention in developing countries may be considered part of a larger debate over whether the global health community has become enamored with the promise of new approaches at the expense of delivering available preventives today. Pap screening, which is feasible anywhere cervical screening is appropriate, is the only intervention currently available for the prevention of cervical cancer in developing countries, and the Pap test will be an essential component of future novel preventive approaches. Cervical cancer vaccination, the long-term effectiveness of which is uncertain, will not eliminate screening requirements and is currently not affordable in developing countries. Root cause analyses, which may appropriately inform the best routes for improving health in developing countries, document that failures of cervical cancer prevention efforts are not attributable to factors specific to the Pap test but to lapses in programmatic quality management to which all screening tests are vulnerable. The genuine promise of cervical cancer prevention for all the world's women therefore resides in skilled quality management rather than novel screening approaches. We propose a global consensus policy by which Pap screening services will be provided in any setting where cervical screening is appropriate but unavailable, with consideration given to novel preventive approaches as they mature. Opportunity costs, borne by the underserved, are associated with prioritizing research on new approaches in any setting where established preventives are feasible but unavailable.


RNA decay machines: the exosome.
The multisubunit RNA exosome complex is a major ribonuclease of eukaryotic cells that participates in the processing, quality control and degradation of virtually all classes of RNA in Eukaryota. All this is achieved by about a dozen proteins with only three ribonuclease activities between them. At first glance, the versatility of the pathways involving the exosome and the sheer multitude of its substrates are astounding. However, after fifteen years of research we have some understanding of how exosome activity is controlled and applied inside the cell. The catalytic properties of the eukaryotic exosome are fairly well described and attention is now drawn to how the interplay between these activities impacts cell physiology. Also, it has become evident that exosome function relies on many auxiliary factors, which are intensely studied themselves. In this way, the focus of exosome research is slowly leaving the test tube and moving back into the cell. The exosome also has an interesting evolutionary history, which is evident within the eukaryotic lineage but only fully appreciated when considering similar protein complexes found in Bacteria and Archaea. Thus, while we keep this review focused on the most comprehensively described yeast and human exosomes, we shall point out similarities or dissimilarities to prokaryotic complexes and proteins where appropriate. The article is divided into three parts. In Part One we describe how the exosome is built and how it manifests in cells of different organisms. In Part Two we detail the enzymatic properties of the exosome, especially recent data obtained for holocomplexes. Finally, Part Three presents an overview of the RNA metabolism pathways that involve the exosome. This article is part of a Special Issue entitled: RNA Decay mechanisms.


Closing Editorial: Conversations in healthcare education.
This article was migrated. The article was marked as recommended. The theme coincided with the 8 thInternational Clinical Skills Conference held in Prato Italy, May 2019. The conference focused on putting the spotlight on conversations in healthcare and we were highly successful in achieving this aim by generating much discussion, debate and dialogue amongst our conference delegates. The conference is known for its informality, friendliness and ability to bring people together as a community of practice and this year was no exception. The conversations on twitter alone was unprecedented with over three million impressions over the period of the conference. This is a truly remarkable number given that the conference is limited to only 250 delegates because of the size of the venue. Whilst the conference did not generate as many paper submissions to MedEdPublish as we would have liked, the five papers submitted were noteworthy and included practical tips to use for teaching intrinsic skills to physicians ( LaFleur et al., 2019), implementing a collaborative social media platform in obstetrics and gynaecology ( O'sullivan, Janssens and Warhurst, 2019), and developing consultation skills for medical students ( Andersson et al., 2019). Nevertheless, we believe this is the first experiment in true 360-degree scientific peer review. A system where manuscripts published on the journal's website before a conference can be explained in conference presentations, questions asked, discussed on social media and finally reviews published alongside the paper on the website. Such a model must surely be beneficial for disseminating new research and ensuring it is of the highest standard. Conversations in healthcare today continue to be of great importance to the future of clinical education and for developing health professionals with the skills needed for person-centred care and we look forward to continuing this work into the future.


Coherence freeze in an optical lattice investigated via pump-probe spectroscopy.
Motivated by our observation of fast echo decay and a surprising coherence freeze, we have developed a pump-probe spectroscopy technique for vibrational states of 85Rb atoms in an optical lattice to gain information about the memory dynamics of the system. We monitor the time-dependent changes of frequencies experienced by atoms and characterize the probability distribution of these frequency trajectories. We show that the inferred distribution, unlike a naive microscopic model of the lattice, correctly predicts the main features of the observed echo decay.


Cost-benefit analysis involving addictive goods: contingent valuation to estimate willingness-to-pay for smoking cessation.
The valuation of changes in consumption of addictive goods resulting from policy interventions presents a challenge for cost-benefit analysts. Consumer surplus losses from reduced consumption of addictive goods that are measured relative to market demand schedules overestimate the social cost of cessation interventions. This article seeks to show that consumer surplus losses measured using a non-addicted demand schedule provide a better assessment of social cost. Specifically, (1) it develops an addiction model that permits an estimate of the smoker's compensating variation for the elimination of addiction; (2) it employs a contingent valuation survey of current smokers to estimate their willingness-to-pay (WTP) for a treatment that would eliminate addiction; (3) it uses the estimate of WTP from the survey to calculate the fraction of consumer surplus that should be viewed as consumer value; and (4) it provides an estimate of this fraction. The exercise suggests that, as a tentative first and rough rule-of-thumb, only about 75% of the loss of the conventionally measured consumer surplus should be counted as social cost for policies that reduce the consumption of cigarettes. Additional research to estimate this important rule-of-thumb is desirable to address the various caveats relevant to this study.


Cost-effectiveness model for prevention of early childhood caries.
This study presents and illustrates a model that determines the cost-effectiveness of three successively more complete levels of preventive intervention (minimal, intermediate, and comprehensive) in treating dental caries in disadvantaged children up to 6 years of age. Using existing data on the costs of early childhood caries (ECC), the authors estimated the probable cost-effectiveness of each of the three preventive intervention levels by comparing treatment costs to prevention costs as applied to a typical low-income California child for five years. They found that, in general, prevention becomes cost-saving if at least 59 percent of carious lesions receive restorative treatment. Assuming an average restoration cost of $112 per surface, the model predicts cost savings of $66 to $73 in preventing a one-surface, carious lesion. Thus, all three levels of preventive intervention should be relatively cost-effective. Comprehensive intervention would provide the greatest oral health benefit; however, because more children would receive reparative care, overall program costs would rise even as per-child treatment costs decline.


Polypeptide structure and encoding location of the adenovirus serotype 2 late, nonstructural 33K protein.
Radiochemical microsequence analysis of selected tryptic peptides of the adenovirus type 2 33K nonstructural protein has revealed the precise region of the genomic nucleotide sequence that encodes this protein. The initiation codon for the 33K protein lies 606 nucleotides to the right of the EcoRI restriction site at 70.7 map units and 281 nucleotides to the left of the postulated carboxyterminal codon of the adenovirus 100K protein. The coding regions for these two proteins thus overlap; however, the 33K protein is derived from the +1 frame with respect to the postulated 100K reading frame. Our results contradict an earlier published report suggesting that these two proteins share extensive amino acid sequence homology (N. Axelrod, Virology 87:366-383, 1978). The published nucleotide sequence of the Ad2 EcoRI-F fragment (70.7 to 75.9 map units) cannot accommodate in a single reading frame the peptide sequences of the 33K protein that we have determined. Sequence analysis of DNA fragments derived from virus has confirmed the published nucleotide sequence in all critical regions with respect to the coding region for the 33K protein. Consequently, our data are only consistent with the existence of an mRNA splice within the coding region for 33K. Consensus donor and acceptor splice sequences have been located that would predict the removal of 202 nucleotides from the transcripts for the 33K protein. Removal of these nucleotides would explain the structure of a peptide that cannot otherwise be directly encoded by the EcoRI-F fragment. Identification of the precise splice points by peptide sequencing has permitted a prediction of the complete amino acid sequence for the 33K protein.


Radiological cervical spine involvement in patients with rheumatoid arthritis: a cross sectional study.
To investigate the frequency and the severity of radiological cervical spine involvement in patients with rheumatoid arthritis (RA). We investigated 165 consecutive unselected patients with RA who fulfilled the revised American College of Rheumatology criteria for RA. All patients had a complete physical and laboratory evaluation. Patients had a radiological evaluation that included hand and wrist radiographs, as well as cervical spine radiographs in anteroposterior, lateral, and lateral in full flexion views. Hand radiographs were evaluated according to the Larsen criteria, while cervical radiographs were evaluated according to Winfield classification. There were 143 women and 22 men, with a mean age of 59.6 +/- 12.5 and disease duration 12.3 +/- 13.9 years. Positive rheumatoid factor was found in 63.6% of patients. One hundred forty-six patients presented radiological findings related to cervical spine involvement: atlantoaxial subluxations were found in 20.6% and erosions of the odontoid process in 2.4%; none presented vertical subluxation. Subaxial subluxations were found in 43.6%, disc space narrowing at C2-C3, C3-C4, C4-C5 levels in 66.1%, and vertebral plate sclerosis and erosions in 43.6%. Cervical spine radiological involvement is a frequent finding in our patients with RA, but the severity of the disease is rather mild, possibly related to the ethnic background.


Regioselectivity in the Cu(I)-catalyzed [4 + 2]-cycloaddition of 2-nitrosopyridine with unsymmetrical dienes.
The thermal (uncatalyzed) and Cu(I)-catalyzed reactions of 2-nitrosopyridine (PyrNO) with the dienes 1,3-pentadiene, E,E-2,4-hexadienol, and 1-phenylbutadiene are investigated experimentally and computationally. The uncatalyzed reactions of the first two dienes occur with low regioselectivity, while the latter proceeds with complete proximal selectivity. Using the M06/6-311+G(d,p)-SDD method, various concerted transition states for the reactions of 2-nitrosopyridine with (E)-1,3-pentadiene and 1-phenylbutadiene were computed. In quantitative agreement with the experimental findings, (a) no energy difference (0.0 kcal/mol) is found between the most stable transition states, endo-prox-anti and endo-dist-anti, in the pentadiene/PyrNO reaction, leading to nearly equal amounts of prox and dist cycloadducts, and (b) the proximal transition state is strongly favored (by 3.7 kcal/mol) over the distal for the highly selective phenylbutadiene/PyrNO reaction. The regioselectivity of the pentadiene/PyrNO reaction is improved markedly (90:10 dist/prox) when catalyzed by Cu(CH3CN)4(+); (diimine)2Cu(+) catalysts increase selectivity for the proximal product (55-65%). Modest effects of the catalyst nature on regioselectivity are observed in the sorbyl alcohol and 1-phenylbutadiene reactions. The relative affinity of an equilibrating set of (diimine)2Cu(+) complexes for the prox and dist cycloadducts, assessed by ESI-MS, is marginally correlated with the prox/dist product regioselectivity produced by the corresponding catalysts. Transition states in the Cu(CH3CN)4(+)- and Cu(diimine)2(+)-catalyzed reactions are located that account for the observed regioselectivities. Coordination effects on the regioselectivity are derived from FMO orbital interactions and the extent of electron transfer between the Cu center and the coordinated nitroso and diene units.


Age-related Differences in Tumour Characteristics and Prognostic Factors for Disease Progression in Cutaneous Squamous Cell Carcinoma of the Head and Neck.
Guidelines for cutaneous squamous cell carcinoma of the head and neck do not take the age of the patient into account, but instead assume equal tumour characteristics and prognostic factors for poor outcome in younger and elderly patients. The aim of this study was to compare tumour characteristics of younger (< 75 years) and elderly (≥ 75 years) patients and identify age-specific risk factors for progression of disease, comprising local recurrence, nodal metastasis and distant metastasis. Patient and tumour characteristics were compared using χ2 or Fisher's exact tests. Multivariable competing risk analyses were performed to compare risk factors for progression of disease, incorporating the risk of dying before developing progression of disease. A total of 672 patients with primary cutaneous squamous cell carcinoma of the head and neck were retrospectively included. Larger tumour diameter, worse differentiation grade and deeper invasion were observed in older patients. In elderly patients, but not in younger patients, tumour diameter ≥ 40 mm, moderate differentiation grade and an invasion depth ≥ 2 mm were independent risk factors for progression of disease.


Regional cerebral blood flow in weight-restored anorexia nervosa: a preliminary study.
Twenty-one individuals (19 females, two males) with teenage-onset anorexia nervosa (AN), 19 of whom were weight restored, were assessed using single-photon emission computed tomography (SPECT) 7 years after onset of AN, at a mean age of 22 years. For comparison we recruited a younger group without neuropsychiatric disorder (mean age 9:8 years; five females, four males) who underwent SPECT at follow-up after an operation for coarctation of the aorta or because of lymphatic leukaemia. Ethical considerations precluded the study of regional cerebral blood flow (rCBF) in participants with completely normal development. The group with AN showed marked hypoperfusion of temporal, parietal, occipital, and orbitofrontal lobes compared to the contrast group. rCBF was not correlated to body mass index in any of the groups. Results suggest that, even long after re-feeding has occurred, AN may be associated with moderate to severe cerebral blood flow hypoperfusion in the temporoparietal (or temporoparietooccipital) region and in the orbitofrontal region. A limitation of the study is that the young contrast group in this study could be expected to have a higher global rCBF than the group with AN. However, this should not significantly affect the relative values used in this study.


Laparoscopic gastric bypass is superior to adjustable gastric band in super morbidly obese patients: A prospective, comparative analysis.
Outcome following laparoscopic adjustable gastric banding (LAGB) in super morbidly obese patients is significantly worse compared with the standard laparoscopic Roux-en-Y gastric bypass (LRYGB). Prospective case series. Community teaching hospital (490 beds). A prospectively maintained database identified patients who underwent operative treatment for morbid obesity between February 2001 and June 2004. The study group included super morbidly obese patients (body mass index >50 [calculated as weight in kilograms divided by the square of height in meters]) following LAGB and LRYGB. Among 106 patients with super morbid obesity, 60 (57%) and 46 (43%) underwent LAGB and LRYGB, respectively. Patient demographics, weight loss, percentage of excess weight loss, change in body mass index, early (<30 days) and late (> or =30 days) complications, reoperations, medical comorbidity, and patient satisfaction were studied. Analysis was performed using the t test and Pearson chi 2 analysis. Overall median follow-up was 16.2 months (range, 1-40 months). Preoperative factors of patient age, sex, weight, body mass index, and medical comorbidity were similar between the 2 groups. Compared with LRYGB, patients who underwent LAGB experienced a greater incidence of late complications (P < .05), reoperations (P < .04), less weight loss (P<.001), and decreased overall satisfaction (P < .006). Likewise, patients who underwent LRYGB had a greater resolution of concomitant diabetes mellitus (P < .05) and sleep apnea (P<.01) compared with the LAGB group. Furthermore, postoperative adjustments to achieve consistent weight loss for LAGB recipients ranged from 1 to 15 manipulations. Our single mortality was in the LAGB group. In super morbidly obese patients, LAGB is significantly associated with more late complications, reoperations, less weight loss, less reduction of medical comorbidity, and patient dissatisfaction compared with LRYGB. Further evaluation of LAGB in this patient population appears warranted.


MiR-301b promotes the proliferation, mobility, and epithelial-to-mesenchymal transition of bladder cancer cells by targeting EGR1.
We investigated the role of miR-301b in the modulation of the proliferation, migration, and invasion of bladder cancer (BLCA) cells. The expression of miR-301b and EGR1 (early growth response gene 1) mRNA were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). A dual-luciferase reporter gene system was used to identify the target relationship between miR-301b and EGR1. Cell proliferation, cell cycle, and apoptosis were analyzed by MTT assay, colony-forming assay, and flow cytometry, respectively. Cell motility and invasiveness were assessed by wound healing and Transwell assays. The expression of proteins involved in epithelial-to-mesenchymal transition (EMT) and EGR1 were determined by Western blot. Our results showed that miR-301b was up-regulated while EGR1 was down-regulated in BLCA tissues compared with adjacent normal tissues. The proliferation, migration, and invasiveness of T24 cells (a kind of human BLCA cell) were suppressed by decreasing miR-301b expression or increasing EGR1 expression. In addition, miR-301b promoted EMT signaling by influencing the expression of related proteins. In conclusion, miR-301b promotes the proliferation, migration, and aggressiveness of human BLCA cells by inhibiting the expression of EGR1.


[Simultaneous determination of phosphorous by-products and inorganic anions in glyphosate mother liquor by ion chromatography with suppressed-conductivity detection].
The by-product anion content was an important index for the evaluation of pesticide glyphosate's productivity technology. A method was developed for the simultaneous determination of glyphosate, phosphorous by-products and other trace impurity anions in the mother liquor of glyphosate procedure by ion chromatography (IC). The sample was diluted with deionized water and filtrated by 0.22 microm nylon filter membrane, and then analyzed by IC directly without anymore pretreatment. The analytical column was Dionex IonPac AS11-HC (250 mm x 4 mm) with a guard column IonPac AG11-HC (50 mm x 4 mm). Gradient KOH eluent generated by an eluent generation cartridge was used at a flow rate of 1.0 mL/min. The detection was performed by a Dionex suppressed conductivity detector. The quantitative analysis of external standard calibration curves was used. The linear ranges of the method for glyphosate, methyl glyphosate, hexamethylphosphoramide (HMPA), glyphosine, phosphite, phosphate, chloride and sulfate were 0.1 - 20 mg/L (r = 0.9995), 0.1 - 20 mg/L (r = 0.9993), 0.1 - 50 mg/L (r = 0.9999), 0.25 - 50 mg/L ( r = 0.9998), 0.05 - 20 mg/L (r = 0.9999), 0.2 - 50 mg/L ( r = 0.9985), 0.02 - 20 mg/L (r = 0.9999) and 0.05 - 50 mg/L (r = 0.9980), respectively. The average recoveries were 93.7% - 104.0% with the relative standard deviations less than 2.5% (n = 7), and the detection limits (S/N = 3) were 0.002 - 0.025 mg/L. The method has been applied to determine the contents of glyphosate, phosphorous by-products and inorganic anions in the mother liquor of glyphosate with satisfactory results.


Human tear fluid protects against Pseudomonas aeruginosa keratitis in a murine experimental model.
Pseudomonas aeruginosa keratitis is an acute sight-threatening infection. We previously reported that human tear fluid could protect individual human corneal epithelial cells in vitro against invasion by and cytotoxicity due to clinical and laboratory isolates of P. aeruginosa and that the protective mechanism was independent of bacteriostatic activity. In the present study, we examined the effects of human tear fluid in vivo. Tears were collected from healthy human volunteers and were studied in vivo in mice. The effects on the virulence of both invasive and cytotoxic clinical isolates of P. aeruginosa were examined. Tear fluid was found to reduce the severity of disease when corneas were challenged with cytotoxic bacteria immediately after scratch injury, and it completely protected against susceptibility to infection by a cytotoxic strain in a model in which corneas were infected during the healing process 6 h after scratching. Visible protection correlated with the inhibition of bacterial colonization 1, 4, and 48 h postinoculation. Tear fluid also significantly reduced the severity of infections caused by invasive P. aeruginosa in the 6-h-healing model. This result also coincided with significantly reduced bacterial colonization at 48 h. In vitro, human tear fluid significantly reduced the ability of invasive and cytotoxic bacteria to translocate across corneal epithelia and increased transepithelial resistance with or without bacterial inoculation. These data show that human tear fluid can protect against P. aeruginosa corneal infection in vivo and that the mechanism likely involves enhanced epithelial barrier function in addition to protection of individual epithelial cells against bacterial internalization and cytotoxicity.


Scientific progress as increasing verisimilitude.
According to the foundationalist picture, shared by many rationalists and positivist empiricists, science makes cognitive progress by accumulating justified truths. Fallibilists, who point out that complete certainty cannot be achieved in empirical science, can still argue that even successions of false theories may progress toward the truth. This proposal was supported by Karl Popper with his notion of truthlikeness or verisimilitude. Popper's own technical definition failed, but the idea that scientific progress means increasing truthlikeness can be expressed by defining degrees of truthlikeness in terms of similarities between states of affairs. This paper defends the verisimilitude approach against Alexander Bird who argues that the "semantic" definition (in terms of truth or truthlikeness alone) is not sufficient to define progress, but the "epistemic" definition referring to justification and knowledge is more adequate. Here Bird ignores the crucial distinction between real progress and estimated progress, explicated by the difference between absolute (and usually unknown) degrees of truthlikeness and their evidence-relative expected values. Further, it is argued that Bird's idea of returning to the cumulative model of growth requires an implausible trick of transforming past false theories into true ones.


Thromboprophylaxis in medical patients: the role of low-molecular-weight heparin.
Many hospitalised medical patients are at increased risk of venous thromboembolism (VTE). Consensus statements recommend that such patients be assessed for risk of VTE on admission to hospital and receive thromboprophylaxis where appropriate. However, VTE prophylaxis is not widely used in medical patients. One explanation is that assessing medical patients' risk of VTE is complicated. The risk depends not only on the current illness but also on multiple intrinsic factors, and a variety of strategies for identifying patients who should receive thromboprophylaxis have been suggested. Thromboprophylaxis with unfractionated heparin (UFH) has proved to be effective in reducing the incidence of deep-vein thrombosis and overall mortality in medical patients. Clinical trial evidence, including a meta-analysis, suggests that thromboprophylaxis with low-molecular-weight heparin (LMWH) is at least as effective as with UFH, and also has the advantage of fewer bleeding complications. In particular, two large, randomised clinical trials--Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) and Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT)--showed that thromboprophylaxis with the LMWHs enoxaparin (40 mg s.c. once daily) or dalteparin (5,000 IU once daily) is more effective than placebo and well tolerated in medical patients. In addition, the Thromboembolism-Prevention in Cardiopulmonary Diseases with Enoxaparin (THE-PRINCE) trial showed that enoxaparin treatment was as effective as UFH. These studies provide solid evidence for the widespread use of thromboprophylaxis in medical patients.


Institutional processes and individual responses: women's experiences of care in relation to cesarean birth.
Cesarean section is an increasingly common mode of birth, and although clinical care has improved and the risks reduced, less attention has been paid to the effect of the procedure and the care received. The aim of this study was to gain a better understanding by investigating individual women's recent experiences and reflections on their care. Views of women who had recently undergone cesarean birth were obtained in a study in which a random sample of women was selected by means of birth registrations in England and invited to complete a questionnaire 3 months after the birth. Text responses to open-ended questions about care during labor and birth, the postnatal period in hospital, and anything else women wished to say about their maternity care were analyzed using qualitative methods. A response rate of 63 percent was achieved; 23 percent of women (n = 682) had a cesarean section birth, 53 percent of which were because of unforeseen problems in labor. A total of 66 percent of women who had a cesarean section responded to one or more open questions. Anticipated themes that were confirmed related to expectations, uncertainty, emotional reactions, pain and discomfort, explanations, support, and adjustment. Emerging themes included "being heard,""how it might have been different,""wasted effort,""just another mother,""wounds and hurt feelings," and "needing to talk." Women responded as individuals and despite different clinical circumstances, the role of the staff and the institutions in which care was provided were key factors in the way most women constructed their cesarean section experience. The themes described present a powerful argument and reminder about why health professionals working in maternity care need to continue to listen to women.


Respondent-driven sampling to recruit MDMA users: a methodological assessment.
Recruiting samples that are more representative of illicit drug users is an on-going challenge in substance abuse research. Respondent-driven sampling (RDS), a new form of chain-referral sampling, is designed to eliminate the bias caused by the non-random selection of the initial recruits and reduce other sources of bias (e.g. bias due to volunteerism and masking) that are usually associated with regular chain-referral sampling. This study provides a methodological assessment of the application of RDS among young adult MDMA/ecstasy users in Ohio. The results show that the sample compositions converged to equilibrium within a limited number of recruitment waves, independent of the characteristics of the initial recruits (i.e. seeds). The sample compositions approximated the theoretical equilibrium compositions, and were not significantly different from the estimated population compositions-with the exception that White respondents were over-sampled and Black respondents were under-sampled. The effect of volunteerism and masking on the sampling process was found not to be significant. Though identifying productive seeds and improving the referral rate are significant challenges when implementing RDS, the findings demonstrate that RDS is a flexible and robust sampling method. RDS has the potential to be widely employed in studies of illicit drug-using populations.


Pain perception and expectation related to interradicular mini-implants insertion: a systematic review and meta-analysis.
The aim of this systematic review was to compare the expectation and perception of pain reported by patients before and after the installation of interradicular mini-implants. Electronic search was performed in six databases. Inclusion criteria were randomized controlled trials (RCTs) or non-randomized controlled clinical trials (nRCTs); studies using mini-implants in the interradicular region; assessment of pain intensity by visual analogue or numerical scale. The risk of bias assessment was based on the Rob 2 tool and Robins-I. A total of 1566 articles were retrieved, and 21 met the eligibility criteria. Six were classified as high risk, one as critical and the other one as uncertain, according to the Robins-I tool. In articles evaluated by the Rob2 tool, ten were classified as serious risk and three as moderate risk. A meta-analysis was also performed. Weighted means were calculated among the studies using the random-effects model and forest plots were generated. Heterogeneity was assessed through the Q test and I2 statistics. It was observed, with moderate evidence, that on a scale of 0 to 10, the pain expectation (effect size 4.75) is higher than that effectively pain generated by the procedure (effect size 1.94). Pain expectation was greater than that actually generated by the procedure, being almost non-existent 7 days postoperatively. This study may help the clinician to reassure the patient regarding the sensations that could be experienced during and after the installation.


Calcium salts of fatty acids with varying fatty acid profiles in diets of feedlot-finished Bos indicus bulls: impacts on intake, digestibility, performance, and carcass and meat characteristics.
We hypothesized that the inclusion of calcium salts of fatty acid (CSFA) into the diets and the fatty acid (FA) profile of the supplements would impact performance and meat characteristics of Bos indicus bulls. Hence, the objective was to evaluate the effects of CSFA profiles on intake, body weight (BW), carcass, and meat characteristics of feedlot-finished B indicus bulls. Fifty-three Nellore bulls [initial BW 315 ± 5.9 kg and 20 ± 2 mo] were used. At the beginning, 6 bulls were randomly chosen and slaughtered for determination of their BW composition, and the remaining 47 bulls were evaluated during a 140-d experimental period. The bulls were placed in individual pens, blocked according to initial BW and randomly allocated to 1 of the 3 following treatments: (1) control diet containing sugarcane bagasse, ground corn, citrus pulp, peanut meal, and mineral-vitamin mix (CON), (2) CON with the addition of 3.3% of CSFA from soybean oil (CSO), or (3) CON with the addition of a mixture of 3.3% of CSFA from palm, soybean, and cottonseed oils (CPSCO). Diets were offered ad libitum and formulated to be isonitrogenous. Bulls supplemented with CSFA had a greater (P < 0.01) final BW, dry matter intake, average daily gain (ADG), feed efficiency (FE), and FA intake vs. CON. Among carcass parameters, CSFA-supplemented bulls had greater (P < 0.01) carcass ether extract concentration vs. CON bulls. When the CSFA profile was evaluated (CSO vs. CPSCO), CPSCO bulls had a better (P ≤ 0.03) FE, carcass ADG, and hot carcass weight (HCW) vs. CSO bulls. The FA intakes differed among CSFA treatments, as the total saturated, palmitic, and oleic FA intakes were greater for CPSCO (P < 0.01), whereas lower intakes of total unsaturated and polyunsaturated FA (P < 0.01) were observed for CPSCO vs. CSO. Samples from the Longissimus muscle contained greater palmitoleic (P = 0.01) and reduced linoleic (P = 0.02) FA concentrations in CSFA-supplemented bulls vs. CON bulls. In agreement with the FA intakes, CPSCO-supplemented bulls had a greater (P ≤ 0.05) unsaturated FA concentration vs. CSO in Longissimus muscle. In summary, CSFA supplementation improved the performance of finishing B. indicus bulls vs. CON. Moreover, the inclusion of CSFA from palm, soybean, and cottonseed oil benefited the FE, carcass ADG, and HCW compared with the inclusion of CSFA from soybean oil, demonstrating the potential of specific FA for improving the performance and meat quality of B. indicus bulls.


Reconstructing biological networks using conditional correlation analysis.
One of the present challenges in biological research is the organization of the data originating from high-throughput technologies. One way in which this information can be organized is in the form of networks of influences, physical or statistical, between cellular components. We propose an experimental method for probing biological networks, analyzing the resulting data and reconstructing the network architecture. We use networks of known topology consisting of nodes (genes), directed edges (gene-gene interactions) and a dynamics for the genes' mRNA concentrations in terms of the gene-gene interactions. We proposed a network reconstruction algorithm based on the conditional correlation of the mRNA equilibrium concentration between two genes given that one of them was knocked down. Using simulated gene expression data on networks of known connectivity, we investigated how the reconstruction error is affected by noise, network topology, size, sparseness and dynamic parameters. Errors arise from correlation between nodes connected through intermediate nodes (false positives) and when the correlation between two directly connected nodes is obscured by noise, non-linearity or multiple inputs to the target node (false negatives). Two critical components of the method are as follows: (1) the choice of an optimal correlation threshold for predicting connections and (2) the reduction of errors arising from indirect connections (for which a novel algorithm is proposed). With these improvements, we can reconstruct networks with the topology of the transcriptional regulatory network in Escherichia coli with a reasonably low error rate.


Pecking Behavior in Conventional Layer Hybrids and Dual-Purpose Hens Throughout the Laying Period.
To avoid the killing of surplus male layer chickens, dual-purpose hybrids are suggested as an alternative approach. These strains may offer additional advantages compared to conventional laying hens, for instance, a lower tendency to develop injurious pecking behavior. The aim of this study was to assess the behavior, with focus on pecking behavior, of conventional layers (Lohmann Brown plus, LB+) and dual-purpose hens (Lohmann Dual, LD). About 1,845 hens per strain with intact beaks were housed in four stable compartments in aviary systems. Video-based scan sampling of general behaviors and continuous observations of pecking behavior were carried out between 25 and 69 weeks of life. With the exception of "dustbathing" and "scratching," hybrid × time during the laying period affected all of the observed general behaviors [F (2, 89) = 3.92-10.81, P < 0.001-0.05]. With increasing age, the LB+ hens performed more general pecking, more locomotion and less comfort and sitting behavior. General pecking and comfort behavior did not change over time in the LD hens, whereas inactive behaviors increased with age. During continuous observations, a significant hybrid x period interaction was found for all forms of pecking behavior [F (2, 89) = 4.55-14.80, P < 0.001-0.05]. The LB+ hens showed particularly more severe feather pecking (SFP), which increased with age. In contrast, SFP remained exceptionally low in the LD hens throughout production. Therefore, dual-purpose hybrids should be considered as an alternative to both avoid the killing of surplus male chickens and the development of SFP in laying hen production.


Timing and Targeting of Treatment in Left Ventricular Hypertrophy.
In most clinical cases, left ventricular hypertrophy (LVH) occurs over time from persistent cardiac stress. At the molecular level, this results in both transient and long-term changes to metabolic, sarcomeric, ion handling, and stress signaling pathways. Although this is initially an adaptive change, the mechanisms underlying LVH eventually lead to maladaptive changes including fibrosis, decreased cardiac function, and failure. Understanding the regulators of long-term changes, which are largely driven by transcriptional remodeling, is a crucial step in identifying novel therapeutic targets for preventing the downstream negative effects of LVH and treatments that could reverse or prevent it. The development of effective therapeutics, however, will require a critical understanding of what to target, how to modify important pathways, and how to identify the stage of pathology in which a specific treatment should be used.


[Experience of surgical treatment of the patients with post-burn cicatricial gastric stenosis].
Experience of surgical treatment of 48 patients with postburn cicatricial gastric stenosis was presented. In 28 of them the combined gastric and esophageal stricture were reveal. Gastric resection according to Billroth-I was performed in 26 patients, gastroduodenostomy according to Finney--in 4, gastric resection according to Hoffmeister-Finsterer--in 5, gastroenterostomy according to Belfler-Brown--in 10 and other operations--in 3. One patient died. For the treatment of combined stricture esophageal passability was restored using bougienage, optimally--along the ring-like thread-guide, conducted, while performing gastric operation, through the mouth, esophagus, stomach and brought out via microgastrostomy.


Morphological effects of wortmannin on the endosomal system and GLUT4-containing compartments in rat adipose cells.
Studies using functional and pharmacological approaches have implicated PI 3-kinase as a key intermediate in the glucose transport and GLUT4 translocation responses to insulin. Confocal microscopy was used to investigate the effects of the PI 3-kinase inhibitor wortmannin in isolated rat adipose cells. Independent of insulin, wortmannin induces the appearance of phase-lucent vacuoles containing the endosomal markers TfR, Rab4, M6PR, and cellubrevin. When added before or with insulin, wortmannin blocks insulin-stimulated GLUT4 translocation, but does not influence the basal VAMP2-containing GLUT4 compartment. These results substantiate the concept of a specialized basal GLUT4 compartment mostly distinct from that of the recycling receptors. However, when added after insulin, wortmannin induces a rapid redistribution of GLUT4 from the cell surface into those endosomal-derived vacuoles where the GLUT4 co-localize with TfR, Rab4, cellubrevin, and VAMP2, but not with clathrin, M6PR, Golgi complex markers TGN38-mannosidase II and gamma-adaptin, and lysosomal marker lgp-120. Therefore, wortmannin also disrupts insulin-stimulated GLUT4 traffic in the recycling endosomal pathway, at a step distal to the sorting of recycling proteins from late endosomal and TGN markers; wortmannin does not appear to affect internalization from the plasma membrane, and delivery from early to late endosomes or from late endosomes to the TGN. In combination with previous kinetic biochemical studies, these results suggest that: (i) insulin stimulates the exocytosis of GLUT4 through a direct pathway from a specialized basal compartment to the plasma membrane, (ii) during endocytosis in the presence of insulin, GLUT4 is sorted out of the TfR compartment into a separate recycling pathway back to the plasma membrane, and (iii) both of these pathways involve wortmannin sensitive enzymes.


The significance of peritoneal cytology in uterine cervix and endometrial cancer.
The purpose of this study was to determine the incidence of positive peritoneal cytology and to elucidate the prognostic value of peritoneal cytology in patients with uterine cervix and endometrial cancer. The incidence of positive peritoneal cytology was investigated in 642 patients including 339 uterine cervix and 303 endometrial cancers. Survival was estimated by the Kaplan-Meier method in a subgroup of 116 stage II cervix and 199 stage I endometrial cancers, and multivariate analysis using Cox's proportional hazards model was used to identify an independent prognostic factor. The incidence of positive peritoneal cytology was found to be 9% in uterine cervix cancer and 15% in endometrial cancer. The incidence was higher in patients with some clinicopathologic status such as advanced stage, lymph node metastasis, ovarian metastasis, and deeper myometrial invasion. The 5-year survival rate for patients with positive or negative peritoneal cytology was 44 or 80% in stage II cervix cancers and 80 or 92% in clinical stage I endometrial cancers, respectively. Multivariate analysis revealed that independent prognostic determinants were pelvic and paraaortic lymph node metastasis and peritoneal cytology in stage II cervix cancer and peritoneal cytology in stage I endometrial cancer. Proper treatment protocol should be scheduled for patients with positive peritoneal cytology.


Modulation of the catabolic effects of interleukin-1 beta on human articular chondrocytes by transforming growth factor-beta.
The effects of IL-1 beta and TGF-beta on the biosynthesis of extracellular matrix structural components relative to the metalloproteinases and their inhibitor TIMP1 in human articular chondrocytes were investigated. It has been proposed that TGF-beta, acting as a positive regulator of matrix accretion, can counteract the increased loss of cartilage matrix induced by IL-1 beta. To allow a comparison of their effects on mRNA levels for these different components, quantitation by competitive RT/PCR was employed. This method was found to give reproducible estimates of mRNA levels and the observed effects of IL-1 beta and TGF-beta on individual components of this system agree with qualitative data obtained by northern blotting. IL-1 beta had a more pronounced effect on aggrecan mRNA levels than on those for type II collagen. Similar quantitative differences were observed between collagenase and stromelysin mRNA levels. TGF-beta generally counteracted the effects of IL-1 beta, and new steady state levels were attained within 24 h. However, the reversal of IL-1 beta induced suppression of matrix protein mRNA levels appeared more effective than its suppression of the increase in stromelysin and collagenase mRNA levels. Similarly TGF-beta did not reduce the extent of IL-1 beta induced secretion of stromelysin at the protein level. TIMP1 mRNA levels were only slightly reduced by IL-1 beta; however this cytokine effectively suppressed its induction by TGF-beta. The higher concentrations of TGF-beta and longer exposure times required to overcome the suppressive effects of IL-1 beta suggest that the interaction between IL-1 beta and TGF-beta in the regulation of TIMP1 expression follows a different mechanism to that operating for the metalloproteinases and matrix proteins. Thus the overall potential of TGF-beta to inhibit proteolysis is attenuated by its much slower effect on TIMP1 mRNA levels.


Anhedonia as a clinical correlate of inflammation in adolescents across psychiatric conditions.
Objectives: Peripheral inflammation has been associated with multiple psychiatric disorders, particularly with depression. However, findings remain inconsistent and unreproducible, most likely due to the disorder's heterogeneity in phenotypic presentation. Therefore, in the present study, in an effort to account for inter-individual differences in symptom severity, we utilised a dimensional approach to assess the relationships between a broad panel of inflammatory cytokines and key psychiatric symptoms (i.e. depression, anhedonia, anxiety, fatigue and suicidality) in adolescents across psychiatric disorders. We hypothesised that only anhedonia (reflecting deficits of reward function) will be associated with inflammation.Methods: Participants were 54 psychotropic medication-free adolescents with diverse psychiatric conditions and 22 healthy control (HC) adolescents, aged 12-20. We measured 41 cytokines after in vitro lipopolysaccharide stimulation. Mann-Whitney U and Spearman correlation tests examined group comparison and associations, respectively, while accounting for multiple comparisons and confounds, including depression severity adolescent.Results: There were no group differences in cytokine levels. However, as hypothesised, within the psychiatric group, only anhedonia was associated with 19 cytokines, including haematopoietic growth factors, chemokines, pro-inflammatory cytokines, and anti-inflammatory cytokines.Conclusions: Our findings suggest that general inflammation may induce reward dysfunction, which plays a salient role across psychiatric conditions, rather than be specific to one categorical psychiatric disorder.


The body beyond the body: expectation of a sensory event is enough to induce ownership over a fake hand.
More than 100 papers have been published on the rubber hand illusion since its discovery 14 years ago. The illusion has been proposed as a demonstration that the body is distinguished from other objects by its participation in specific forms of intermodal perceptual correlation. Here, we radically challenge this view by claiming that perceptual correlation is not necessary to produce the experience of this body as mine. Each of 15 participants was seated with his/her right arm resting upon a table just below another smaller table. Thus, the real hand was hidden from the participant's view and a life-sized rubber model of a right hand was placed on the small table in front of the participant. The participant observed the experimenter's hand while approaching--without touching--the rubber hand. Phenomenology of the illusion was measured by means of skin conductance response and questionnaire. Both measures indicated that participants experienced the illusion that the experimenter's hand was about to touch their hidden hand rather than the rubber hand, as if the latter replaced their own hand. This did not occur when the rubber hand was rotated by 180° or replaced by a piece of wood. This illusion indicates that our brain does not build a sense of self in a merely reactive way, via perceptual correlations; rather it generates predictions on what may or may not belong to itself.


High-order modulation on a single discrete eigenvalue for optical communications based on nonlinear Fourier transform.
In this paper, we experimentally investigate high-order modulation over a single discrete eigenvalue under the nonlinear Fourier transform (NFT) framework and exploit all degrees of freedom for encoding information. For a fixed eigenvalue, we compare different 4 bit/symbol modulation formats on the spectral amplitude and show that a 2-ring 16-APSK constellation achieves optimal performance. We then study joint spectral phase, spectral magnitude and eigenvalue modulation and found that while modulation on the real part of the eigenvalue induces pulse timing drift and leads to neighboring pulse interactions and nonlinear inter-symbol interference (ISI), it is more bandwidth efficient than modulation on the imaginary part of the eigenvalue in practical settings. We propose a spectral amplitude scaling method to mitigate such nonlinear ISI and demonstrate a record 4 GBaud 16-APSK on the spectral amplitude plus 2-bit eigenvalue modulation (total 6 bit/symbol at 24 Gb/s) transmission over 1000 km.


Fractionated radiation alters oncomir and tumor suppressor miRNAs in human prostate cancer cells.
We have previously demonstrated that prostate carcinoma cells exposed to fractionated radiation differentially expressed more genes compared to single-dose radiation. To understand the role of miRNA in regulation of radiation-induced gene expression, we analyzed miRNA expression in LNCaP, PC3 and DU145 prostate cancer cells treated with single-dose radiation and fractionated radiation by microarray. Selected miRNAs were studied in RWPE-1 normal prostate epithelial cells by RT-PCR. Fractionated radiation significantly altered more miRNAs as compared to single-dose radiation. Downregulation of oncomiR-17-92 cluster was observed only in the p53 positive LNCaP and RWPE-1 cells treated with single-dose radiation and fractionated radiation. Comparison of miRNA and mRNA data by IPA target filter analysis revealed an inverse correlation between miR-17-92 cluster and several targets including TP53INP1 in p53 signaling pathway. The base level expressions of these miRNAs were significantly different among the cell lines and did not predict the radiation outcome. Tumor suppressor miR-34a and let-7 miRNAs were upregulated by fractionated radiation in radiosensitive LNCaP (p53 positive) and PC3 (p53-null) cells indicating that radiation-induced miRNA expression may not be regulated by p53 alone. Our data support the potential for using fractionated radiation to induce molecular targets and radiation-induced miRNAs may have a significant role in predicting radiosensitivity.


Targeted next generation sequencing as a tool for precision medicine.
Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response. A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms. Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy. PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.


Protein Phosphatases: A Neglected Target Family for Drug Discovery.
The gene family of protein phosphatases is a rich but under-exploited source of therapeutically validated drug targets modulating signal transduction pathways. Unlike the kinase family, research and development activities have not yet yielded any approved small-molecule drugs against a phosphatase. Approximately 20 years ago, the phosphatase family was classified as undruggable and intractable. This was primarily due to the spectacular failure of the cumulated industry-wide drug discovery efforts to develop PTP1B inhibitors. Recently, allosteric inhibitors against SHP2, a member of the phosphatase family, have entered clinical trails, which has reawakened industry's interest towards this neglected enzyme family. This contribution reviews the recent R&D trends around small-molecule efforts towards phosphatase modulators over the last years, rather than providing an exhaustive review of the field of allosteric phosphatase inhibitors.


Extrapulmonary tuberculosis: experience at Veterans General Hospital-Taipei, 1985 to 1987.
From 1985 to 1987, 343 cases of extrapulmonary tuberculosis (TB) were identified, representing about 20% of all the newly diagnosed TB cases at Veterans General Hospital-Taipei. Bacteriological and histopathological examinations were of equal importance in making a diagnosis of extrapulmonary TB. However, 79% of the cases of TB meningitis were diagnosed only by positive cerebrospinal fluid cultures for Mycobacterium tuberculosis. The pleura, lymph nodes, urinary and osteoarticular systems were the most commonly affected locations. Male patients predominated except for TB lymphadenitis. However, female patients with TB are more likely to have non-respiratory TB than are male patients. The peak number of cases by age occurred in the seventh decade of life, and the mean age of male patients was older than that of female patients. Pulmonary lesions suggestive of TB and age over 60 years were the two most common risk factors. Anti-TB chemotherapy alone was enough in many patients. However, more than 50% of the patients with osteoarticular TB, pericardial TB, TB lymphadenitis, and TB enteritis or peritonitis underwent surgical intervention for either diagnosis or treatment. The results of adequate anti-TB chemotherapy or surgical treatment were usually satisfactory. About 32% of the patients were lost to follow-up before completing anti-TB chemotherapy. In this series, 34 deaths occurred, of which 7 were TB-unrelated and 10 occurred before a diagnosis of TB was made or proper therapy initiated. Although TB meningitis was uncommon in this series, it had the highest mortality rate (67%).


Sensitivity of naturally occurring coliphages to type I and type II restriction and modification.
Protection against lethal infections by bacteriophage may seem the most likely role of restriction-modification (R-M) systems in bacteria and the reason for their evolution. There are, however, phenomena which question this phage-mediated selection hypothesis for the maintenance of extant R-M systems. Most prominent among these are the mechanisms phage have to avoid or otherwise limit the effects of the restriction endonucleases produced by their host bacteria. To evaluate the importance of these antirestriction mechanisms in Escherichia coli, we have examined the sensitivity of coliphage from natural and laboratory sources to a series of type I and II R-M systems. The results of our study indicate that, in vivo, restriction endonucleases have no effect on a substantial fraction of naturally occurring coliphage. The absence of restriction sites appears to be the most common reason why these phage are unaffected by type II restriction endonucleases, but other antirestriction mechanisms also operate. On the other hand, the frequency of naturally occurring coliphage sensitive to restriction appears sufficiently great for phage-mediated selection to be a viable hypothesis for the maintenance of R-M in E. coli and its accessory elements.


Wnt/frizzled signalling modulates the migration and differentiation of immortalized cardiac fibroblasts.
The Wnt/frizzled (Fzd) signal transduction cascade has been implicated in the proliferation, differentiation, and migration of many cell types, but the role of this pathway in cardiac fibroblast differentiation is not known. Our lab previously showed an up-regulation of Fzd-1 and -2 expression in myofibroblasts after myocardial infarction (MI), indicating a potential role for the Fzd receptor in fibroblast-myofibroblast differentiation. The present study was performed to further define the role of specific Wnt and Fzd proteins in the proliferation, migration, and differentiation of cardiac fibroblasts. Because primary fibroblasts become senescent after a few passages and are difficult to transfect, we immortalized rat cardiac fibroblasts with telomerase [cardiac fibroblasts immortalized with telomerase (CFIT)]. Proliferation of CFIT was not significantly influenced by Wnt/Fzd signalling. The migration, however, was attenuated by all Wnt/Fzd combinations tested. Also, specific Wnt/Fzd combinations modulated the expression of the following myofibroblast markers: collagen Ialpha1, collagen III, fibronectin and its splice variants, and alpha-smooth muscle actin. The results indicate that myofibroblast migration and differentiation, but not proliferation, can be modulated by interventions in Wnt/Fzd signalling. Therefore, Wnt/Fzd signalling may serve as a novel therapeutic target to ameliorate wound healing after MI.