Membrane currents of cultured rat sympathetic neurons under voltage clamp.
Sympathetic neurons, dissociated from neonatal rat superior cervical ganglia, were voltage clamped with two microelectrodes. Depolarization from resting potential activated a rapid transient inward current carried by sodium and a slow inward current blocked by cobalt. Depolarization from resting potential also activated up to three kinetically distinct outward currents, which were further studied by tail current analysis. Following long depolarizing steps, outward current decayed biphasically. The fast phase (delayed rectifier) decayed over 10-20 ms. The slow phase (calcium dependent) required as much as 1-2 s to decay to base line. A small component of the total outward current was a persistent current activated between -70 and -30 mV (M-current), which decayed over 200-300 ms. This current was studied in isolation following hyperpolarizing steps from potentials negative to the threshold for activation of the other delayed outward currents. Tetraethylammonium (TEA) blocked the fast tail current, partially inhibited the slow tail current, and reduced M-currents. Cobalt selectively decreased the slow tail current. Muscarine blocked M-current but not other outward currents. A transient outward current was activated by depolarization from only holding potentials negative to -60 mV. This current peaked in 10-20 ms and decayed over about 50 ms. A persistent ("anomalous") inward current was evoked by hyperpolarizing steps from only holding potentials negative to -50 to -60 mV. These seven membrane currents may be separately characterized on the basis of their voltage- and time-dependent properties. Further identification is aided by the use of channel-blocking chemicals, although the latter may lack specificity, especially when used to study potassium channels.


Brentuximab vedotin for refractory anaplastic lymphoma kinase-negative anaplastic large cell lymphoma in leukemic phase with RUNX3 overexpression.
Anaplastic lymphoma kinase (ALK)- negative anaplastic large cell lymphoma (ALCL) is an aggressive CD30-positive non- Hodgkin lymphoma. ALK-ALCL rarely manifests with extensive bone marrow and peripheral blood involvement (known as "leukemic phase"). A 54-year-old woman was diagnosed with ALK-ALCL in leukemic phase, characterized by an extremely poor prognosis. Lymphoma cells in this case showed chromosomal translocation 1p36.1- encoded RUNX3 and overexpression of its protein. She was refractory to CHOP and salvage chemotherapy. Fortunately, she achieved complete remission with three cycles of Brentuximab vedotin (BV) and underwent umbilical cord blood transplantation. However, she died due to treatment-related mortality on day 129. The autopsy findings showed no lymphoma cells. Treatment strategy for ALK-ALCL is controversial, but the efficacy of BV in CD30-positive peripheral T-cell lymphoma not only as salvage regimens, but also in first line, has been reported in recent years. BV may be an effective option for ALK-ALCL in leukemic phase.


Role of diffusion tensor imaging in resection of thalamic juvenile pilocytic astrocytoma.
The choice of surgical approach during resection of a thalamic juvenile pilocytic astrocytoma (JPA) is dictated by the location of the displaced normal thalamus and posterior limb of the internal capsule (PLIC). Diffusion tensor (DT) imaging and white matter tractography can identify the location of the PLIC in relation to the tumor and may be useful in planning the operative trajectory. Diffusion tensor imaging was used to localize the PLIC on preoperative MR imaging in 6 children undergoing resection of thalamic JPAs. After review of the standard T2-weighted MR imaging sequences, the anticipated position of the PLIC was determined. This result was compared with the location of the PLIC determined by a blinded radiologist with the use of DT imaging. The utility of DT imaging in determining the surgical approach to a thalamic JPA, degree of resection, and neurological outcomes were all evaluated. Diffusion tensor imaging confirmed the expected location of the PLIC as approximated on conventional T2-weighted images in all 6 cases. In 1 patient in particular, unexpected medial deviation of the PLIC was identified, and this proved useful in tailoring the approach to a more lateral trajectory. Gross-total resection of all cystic and solid tumor components was confirmed on postoperative imaging in all cases. All patients experienced mild to moderate worsening of neurological status immediately following resection, but 4 of 6 patients were back to their preoperative baseline at 6-month follow-up. Diffusion tensor imaging and white matter tractography successfully identified the white matter fibers emanating from the precentral gyrus within the PLIC in children with thalamic JPAs prior to surgery. Diffusion tensor imaging served as a valuable tool for stereotactic planning of operative approaches to thalamic JPAs. Localizing the position of the PLIC helped minimize potential neurological morbidity and facilitated gross-total resection.


Relationship between mechanical properties and pentosidine in tendon: effects of age, diet restriction, and aminoguanidine in broiler breeder hens.
Nonenzymatic glycosylation contributes to the formation of crosslinks, which leads to the structural and functional deterioration of tissue protein. The accumulation of these crosslinks in tissue proteins has been implicated in the alteration of biomechanical properties of connective tissues. The objective of this study was to determine whether tendon breaking time (TBT) and tendon breaking strength (TBS) of the flexor perforans et perforatus digiti iii tendon were related to concentrations of pentosidine in tendons (Pt) of broiler breeder hens from 8 to 125 wk of age. In addition, effects of diet restriction (DR) and a crosslinking inhibitor, aminoguanidine (AG) on Pt, TBS, and TBT were determined. Female chicks (n = 450) were randomly assigned to four treatment groups immediately after hatch: ad libitum-fed (AL); diet-restricted (DR; 60% of AL); and AL and DR groups supplemented with 1.35 mg/kg BW per day AG in the feed (AL+AG and DR+AG, respectively). In AL hens, Pt increased with increasing age (P < or = 0.0001). Concurrently, an age-related parallel increase was found for TBS (P < or = 0.0001) and TBT (P < or = 0.0001). Rate of Pt accumulation was lower in DR (P < or = 0.001), TBS (P < or = 0.01), and TBT (P < or = 0.02) hens compared with AL hens. Concentration of Pt in the AL + AG group was lower (P < or = 0.0002) than in the AL group; TBS and TBT (P < or = 0.01) followed a similar pattern. Supplementation of DR with AG did not affect Pt, TBS, or TBT. The age-related increase in Pt and loss of elasticity in the tendon was retarded by diet restriction and AG.


Passive, continuous monitoring of carbon dioxide geostorage using muon tomography.
Carbon capture and storage is a transition technology from a past and present fuelled by coal, oil and gas and a planned future dominated by renewable energy sources. The technology involves the capture of carbon dioxide emissions from fossil fuel power stations and other point sources, compression of the CO2 into a fluid, transporting it and injecting it deep beneath the Earth's surface into depleted petroleum reservoirs and other porous formations. Once injected, the CO2 must be monitored to ensure that it is emplaced and assimilated as planned and that none leaks back to surface. A variety of methods have been deployed to monitor the CO2 storage site and many such methods have been adapted from oilfield practice. However, such methods are commonly indirect, episodic, require active signal generation and remain expensive throughout the monitoring period that may last for hundreds of years. A modelling framework was developed to concurrently simulate CO2 geostorage conditions and background cosmic-ray muon tomography, in which the potential was assessed for using variations in muon attenuation, due to changes in CO2 abundance, as a means of CO2 detection. From this, we developed a passive, continuous monitoring method for CO2 storage sites using muon tomography, the tools for which can be deployed during the active drilling phase (development) of the storage site. To do this, it was necessary to develop a muon detector that could be used in the hostile environment (saline, high temperature) of the well bore. A prototype detector has been built and tested at the 1.1 km deep Boulby potash mine on the northeast coast of England, supported by the existing STFC Boulby Underground Laboratory on the site. The detector is now ready to be commercialized.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.


Whats 'App-ening': the help of new technologies in nutrition in digestive diseases.
The aim of this study is to review the basic concepts of electronic health (eHealth), with a focus on its nutritional applications and its usefulness for digestive diseases. eHealth applications for the treatment and monitoring of digestive disease are growing in number. ehealth helps patients in coping with their disease by promoting self-management, which increases adherence to medical treatment and diets, and leads to an improved quality of life. For irritable bowel syndrome (IBS), there are multiple applications that provide dietary advice, for example, a low FODMAP (Fermentable Oligo, Mono, Disaccharides And Polyols) diet. However, many applications lack a symptom scoring function and do not include a module for assisting the essential reintroduction of high FODMAP foods. In general, there are very few applications that enable direct patient communication with healthcare professionals. A more holistic approach that educates patients and enables them to communicate directly with eCare provider through a web application is one of the functions most requested by patients. eHealth solutions for digestive diseases have a supportive function and a positive impact on patients. However, there is a need to increase patient education and further develop the possibility for care team-patient communication within eHealth solutions.


MR changes in the calcarine area resulting from retinal degeneration.
To study MR images for atrophic changes in the calcarine area resulting from retinal degeneration. MR images from nine patients with retinal degeneration confirmed by ophthalmologic examination and from 30 healthy volunteers were reviewed. The causes of retinal degeneration were hereditary pigmentary degeneration of the retina (four patients), high myopia (two patients), and chorioretinal atrophy (three patients); all patients had visual disturbances and visual field abnormalities. To estimate the morphological changes of the calcarine area, the widths of the right and left calcarine fissures were measured on T1-weighted sagittal images and compared with images from age-matched control subjects. The calcarine fissures were significantly dilated in the patients with retinal degeneration. The anterior and middle points, which represent the peripheral visual field center, were more dilated than the posterior point. The MR findings suggested calcarine atrophy related to retinal degeneration. Transneuronal degenerative changes may occur in the calcarine area after retinal degeneration.


What on-line searches tell us about public interest and potential impact on behaviour in response to minimum unit pricing of alcohol in Scotland.
To investigate whether the introduction of minimum unit pricing (MUP) in Scotland on 1 May 2018 was reflected in changes in the likelihood of alcohol-related queries submitted to an internet search engine, and in particular whether there was any evidence of increased interest in purchasing of alcohol from outside Scotland. Observational study in which individual queries to the internet Bing search engine for 2018 in Scotland and England were captured and analysed. Fluctuations over time in the likelihood of specific topic searches were examined. The patterns seen in Scotland were contrasted with those in England. Scotland and England. People who used the Bing search engine during 2018. Numbers of daily queries submitted to Bing in 2018 on eight alcohol-related topics expressed as a proportion of queries on that day on any topic. These daily likelihoods were smoothed using a 14-day moving average for Scotland and England separately. There were substantial peaks in queries about MUP itself, cheap sources of alcohol and online alcohol outlets at the time of introduction of MUP in May 2018 in Scotland, but not England. These were relatively short-lived. Queries related to intoxication and alcohol problems did not show a MUP peak, but were appreciably higher in Scotland than in England throughout 2018. Analysis of internet search engine queries appears to show that a fraction of people in Scotland may have considered circumventing minimum unit pricing in 2018 by looking for on-line alcohol retailers. The overall higher levels of queries related to alcohol problems in Scotland compared with England mirrors the corresponding differences in alcohol consumption and harms between the countries.


Existential meaning's role in the enhancement of hope and prevention of depressive symptoms.
The authors confirmed that existential meaning has a unique relationship with and can prospectively predict levels of hope and depressive symptoms within a population of college students. Baseline measures of explicit meaning (i.e., an individual's self-reported experience of a sense of coherence and purpose in life) and implicit meaning (i.e., an individual's self-reported embodiment of the factors that are normatively viewed as comprising a meaningful life) explained significant amounts of variance in hope and depressive symptoms 2 months later beyond the variance explained by baseline levels of hope/depression, neuroticism, conscientiousness, agreeableness, openness to experience, extraversion, and social desirability. The authors discuss implications of these findings for the field of mental health treatment and suggest ways of influencing individuals' experience of existential meaning.


Metal-free ALS variants of dimeric human Cu,Zn-superoxide dismutase have enhanced populations of monomeric species.
Amino acid replacements at dozens of positions in the dimeric protein human, Cu,Zn superoxide dismutase (SOD1) can cause amyotrophic lateral sclerosis (ALS). Although it has long been hypothesized that these mutations might enhance the populations of marginally-stable aggregation-prone species responsible for cellular toxicity, there has been little quantitative evidence to support this notion. Perturbations of the folding free energy landscapes of metal-free versions of five ALS-inducing variants, A4V, L38V, G93A, L106V and S134N SOD1, were determined with a global analysis of kinetic and thermodynamic folding data for dimeric and stable monomeric versions of these variants. Utilizing this global analysis approach, the perturbations on the global stability in response to mutation can be partitioned between the monomer folding and association steps, and the effects of mutation on the populations of the folded and unfolded monomeric states can be determined. The 2- to 10-fold increase in the population of the folded monomeric state for A4V, L38V and L106V and the 80- to 480-fold increase in the population of the unfolded monomeric states for all but S134N would dramatically increase their propensity for aggregation through high-order nucleation reactions. The wild-type-like populations of these states for the metal-binding region S134N variant suggest that even wild-type SOD1 may also be prone to aggregation in the absence of metals.


Osmoregulation of thirst and vasopressin release in pregnancy.
Osmoregulation is altered in human gestation, body tonicity declining to a nadir early in pregnancy after which a new steady-state plasma osmolality is maintained until term. Development of precise, sensitive, and specific radioimmunoassays for arginine vasopressin (AVP), which permit clearer definitions of functional properties of the osmoregulatory system, have led to a formulation of how these changes occur (both in women as well as in a gravid rat model). The osmotic thresholds for thirst and antidiuretic hormone release each decrease approximately 10 mosmol/kg during the initial weeks of human gestation. Lowering the threshold to drink stimulates increased water intake and dilution of body fluids. Because AVP release is not suppressed at the usual levels of tonicity, it still circulates and water is retained. Osmolality declines until it decreases below the osmotic thirst threshold (situated several mosmol/kg above that for hormone secretion), and a new steady state, with little change in water turnover, is established. The metabolic clearance rate of AVP is also altered, increasing three- to fourfold between gestational week 10 and midtrimester, paralleling the appearance and rapid rise in circulating cystine-aminopeptidase (vasopressinase), an observation that may explain several disorders of water handling that complicate human pregnancy. Finally, mechanisms responsible for the altered osmoregulation are obscure but chorionic gonadotropin may be involved in the changes during human gestation.


Visual hallucinations in the psychosis spectrum and comparative information from neurodegenerative disorders and eye disease.
Much of the research on visual hallucinations (VHs) has been conducted in the context of eye disease and neurodegenerative conditions, but little is known about these phenomena in psychiatric and nonclinical populations. The purpose of this article is to bring together current knowledge regarding VHs in the psychosis phenotype and contrast this data with the literature drawn from neurodegenerative disorders and eye disease. The evidence challenges the traditional views that VHs are atypical or uncommon in psychosis. The weighted mean for VHs is 27% in schizophrenia, 15% in affective psychosis, and 7.3% in the general community. VHs are linked to a more severe psychopathological profile and less favorable outcome in psychosis and neurodegenerative conditions. VHs typically co-occur with auditory hallucinations, suggesting a common etiological cause. VHs in psychosis are also remarkably complex, negative in content, and are interpreted to have personal relevance. The cognitive mechanisms of VHs in psychosis have rarely been investigated, but existing studies point to source-monitoring deficits and distortions in top-down mechanisms, although evidence for visual processing deficits, which feature strongly in the organic literature, is lacking. Brain imaging studies point to the activation of visual cortex during hallucinations on a background of structural and connectivity changes within wider brain networks. The relationship between VHs in psychosis, eye disease, and neurodegeneration remains unclear, although the pattern of similarities and differences described in this review suggests that comparative studies may have potentially important clinical and theoretical implications.


Recombinant factor VIIa restores aggregation of alphaIIbbeta3-deficient platelets via tissue factor-independent fibrin generation.
Recombinant factor VIIa (rFVIIa) is a safe and effective prohemostatic drug for patients with Glanzmann thrombasthenia (GT). However, the mechanism of action of rFVIIa in these patients is still unclear. Although patients with GT are characterized by a complete absence of platelet aggregation to a variety of agonists, it has been shown that GT platelets are able to form aggregates, provided polymerizing fibrin is present. We studied the effect of rFVIIa-mediated fibrin formation on aggregation of alphaIIbbeta3-deficient platelets. When washed platelets from GT patients or platelets from healthy volunteers treated with an arginyl-glycyl-aspartyl-containing peptide were activated with collagen in the presence of rFVIIa and purified coagulation factors X, II, and fibrinogen, complete aggregation occurred after a lag phase. Fibrin generation proceeded via rFVIIa-mediated thrombin generation on the activated platelet surface independently of tissue factor. Electron microscopic analysis of alphaIIbbeta3-independent platelet aggregates showed a densely packed structure suggestive of a true platelet-fibrin interaction and not via trapping of platelets into a fibrin network. Also, rFVIIa-mediated alphaIIbbeta3-independent aggregation was demonstrated under conditions of flow using a collagen-coated surface. In conclusion, the efficacy of rFVIIa in GT patients might be explained by induction of alphaIIbbeta3-independent platelet aggregation, which compensates the lack of alphaIIbbeta3-dependent aggregation.


Enriching medical trainees' learning through practice: a video reflexive ethnography study protocol.
Supporting medical students' and junior doctors' development in busy clinical settings is challenging. As opportunities for developing trainees, for example, traditional bedside teaching, are decreasing, teaching outside of clinical practice is increasing. However, evidence suggests that effective learning through practice arises via an interplay between, first, what experiences are afforded by clinical settings and, second, how trainees engage with these affordances. Many studies investigating clinician learning through practice focus on only one of these two factors. Yet, a well-recognised methodological challenge of enabling learners to articulate how and what they are learning through practice exists. We need, therefore, to understand how this relationship plays out in practice in ways that enrich learning. This protocol describes a video reflexive ethnographic approach to illuminate how learning through practice in hospital settings occurs and can be enriched. The study will be conducted in two phases. In phase I, senior clinicians from emergency medicine, medicine and surgical specialties will be interviewed about how they guide trainees' learning through practice. These forms of guidance, analysed using the framework method, will inform phase II comprising observations of practice in: (1) emergency, (2) medical and (3) surgical departments. Video recorded episodes of clinicians' guiding learning through practice will be shared and appraised in reflexive sessions with each clinical team. Relational interdependent learning theory informs the design and data analyses to elicit and evaluate strategies for guiding learning through practice. Ethical approval has been received from both healthcare and university settings. The findings should provide important insights for clinicians about workplace learning practices. Findings will be disseminated across the project phases and to diverse audiences-locally, nationally and internationally. The dissemination strategy will use seminars, grand rounds, conference presentations and academic papers to articulate practical, theoretical and methodological findings.


Onychomadesis: A rare adverse effect in early-period valproic acid therapy.
Valproic acid is an effective, frequently used anticonvulsant drug. Typical adverse effects include weight gain, hair loss, and nausea. Hyperpigmentation, onycholysis, and onychomadesis are nail changes that can be seen after valproic acid use. Changes occur at the distal and proximal portions of the nail bed in onycholysis and onychomadesis, respectively. Onychomadesis is a very rare disease of childhood with the exception of systemic and genetic diseases. Here, we present a child aged 23 months, the youngest and the earliest isolated patient with onychomadesis, which occurred after valproic acid treatment and worried the family but resolved spontaneously. The improvement of this very rare adverse effect of antiepileptic drugs after cessation of valproic acid without treatment is emphasized.


LC-MS method for the simultaneous quantitation of the anti-inflammatory constituents in oregano (Origanum species).
Oregano (Origanum spp.), a popular herb in western and Middle Eastern cuisine, was reported to show anti-inflammatory activities in vitro and in vivo but without any information as to the compounds responsible, whether the plants were authenticated or only contained true Origanum spp. Using a wide range of botanically authenticated oregano, we were able to show that oregano had anti-inflammatory activity and then using biodirected-guided fractionation, identified the anti-inflammatory agents in oregano as rosmarinic acid, oleanolic acid, and ursolic acid. In this study, we successfully developed an LC-MS (SIM mode) method to achieve coquantitation of these three organic acids with the application of a unique tandem column system. The detection of rosmarinic acid was optimal under negative ion mode of SIM, whereas oleanolic acid and ursolic acid were sensitive to positive ion mode. The simultaneous quantitation was attained by setting two time segments in one run to facilitate the ESI polarity switch. For the investigated analytes romarinic acid, oleanolic acid, and ursolic acid, good linearities (r(2) > 0.999) were obtained for each calibration curve. Validation for this method showed a precision (relative standard deviation) ranging from 4.84 to 6.41%, and the recoveries varied from 92.2 to 100.8% for the three analytes. A quantitative survey of these anti-inflammatory constituents in different oregano species (O. vulgare ssp. hirtum, O. vulgare, and O. syriacum) and chemotypes within the species varied significantly in their accumulation of rosmarinic, oleanolic, and ursolic acids. Significant variation in chemical composition between species and within a species was found.


The presence of a glycosyl phosphatidylinositol-anchored alpha-mannosidase in boar sperm.
alpha-Mannosidase and beta-galactosidase were released from boar sperm into the medium by treatment with calcium ionophore A23187 or by 0.2% Brij-35/2% acetic acid. About half as much alpha-mannosidase activity as that in the acid extract was recovered by digestion with phosphatidylinositol-specific phospholipase C (PI-PLC), whereas the liberation rate of beta-galactosidase treated with PI-PLC was low. These results suggest that some alpha-mannosidase is anchored in the plasma membrane of the acrosomal region by attachment to the lipid phosphatidylinositol and that beta-galactosidase is localized mainly in the acrosome or integrated in the plasma membrane by a spanning stretch of hydrophobic peptides. beta-Galactosidase, which is present as an oligomers in the acid extract of sperm, dissociated into monomers under weakly alkaline conditions; under acidic conditions, the monomers associated again. No pH-sensitive association-dissociation of alpha-mannosidase was observed.


Glycine inhibits melanogenesis in vitro and causes hypopigmentation in vivo.
The simplest amino acid, glycine, is important in protein composition and plays a significant role in numerous physiological events in mammals. Despite the inhibitory effect of glycine on spontaneous melanogenesis in B16F0 melanoma cells, the details of the underlying mechanisms remain unknown. The present study was conducted to investigate the further effects and the mechanisms of inhibitory effect of glycine on melanogenesis using B16F0 melanoma cells and hair follicle melanogenesis in C57BL/6J mice. Treatment with glycine (1-16 mM) for 72 h inhibited alpha-melanocyte stimulating hormone (alpha-MSH)-induced melanogenesis in a concentration-dependent manner without any effects on cell proliferation in B16F0 melanoma cells. Treatment with kojic acid (2.5 mM) for 72 h also inhibited alpha-MSH-induced melanogenesis in B16F0 melanoma cells. The highest dose of glycine inhibited the alpha-MSH-induced increment of tyrosinase protein levels in B16F0 melanoma cells. In hair follicle melanogenesis in C57BL/6J mice, treatment with glycine (1250 or 2500 mg/kg, i.p.) for 5 d prevented the decrement of L* and C* values and inhibited the increment of tyrosinase protein levels and melanin content within the skin. Treatment with hydroquinone (100 mg/kg, i.p.) for 5 d had a similar hypopigmenting effect to that of high dose glycine. These results suggest that glycine has an inhibitory effect on melanogenesis that is mediated by down-regulation of tyrosinase protein levels, leading to a hypopigmenting effect in C57BL/6J mice.


Quantitative analysis of molecular-level DNA crystal growth on a 2D surface.
Crystallization is an essential process for understanding a molecule's aggregation behavior. It provides basic information on crystals, including their nucleation and growth processes. Deoxyribonucleic acid (DNA) has become an interesting building material because of its remarkable properties for constructing various shapes of submicron-scale DNA crystals by self-assembly. The recently developed substrate-assisted growth (SAG) method produces fully covered DNA crystals on various substrates using electrostatic interactions and provides an opportunity to observe the overall crystallization process. In this study, we investigated quantitative analysis of molecular-level DNA crystallization using the SAG method. Coverage and crystal size distribution were studied by controlling the external parameters such as monomer concentration, annealing temperature, and annealing time. Rearrangement during crystallization was also discussed. We expect that our study will provide overall picture of the fabrication process of DNA crystals on the charged substrate and promote practical applications of DNA crystals in science and technology.


Atomic Structure of the E2 Inner Core of Human Pyruvate Dehydrogenase Complex.
Pyruvate dehydrogenase complex (PDC) is a large multienzyme complex that catalyzes the irreversible conversion of pyruvate to acetyl-coenzyme A with reduction of NAD+. Distinctive from PDCs in lower forms of life, in mammalian PDC, dihydrolipoyl acetyltransferase (E2; E2p in PDC) and dihydrolipoamide dehydrogenase binding protein (E3BP) combine to form a complex that plays a central role in the organization, regulation, and integration of catalytic reactions of PDC. However, the atomic structure and organization of the mammalian E2p/E3BP heterocomplex are unknown. Here, we report the structure of the recombinant dodecahedral core formed by the C-terminal inner-core/catalytic (IC) domain of human E2p determined at 3.1 Å resolution by cryo electron microscopy (cryoEM). The structure of the N-terminal fragment and four other surface areas of the human E2p IC domain exhibit significant differences from those of the other E2 crystal structures, which may have implications for the integration of E3BP in mammals. This structure also allowed us to obtain a homology model for the highly homologous IC domain of E3BP. Analysis of the interactions of human E2p or E3BP with their adjacent IC domains in the dodecahedron provides new insights into the organization of the E2p/E3BP heterocomplex and suggests a potential contribution by E3BP to catalysis in mammalian PDC.


Nitrate sources and the effect of land cover on the isotopic composition of nitrate in the catchment of the Rhône River.
The Rhône River originates in the high Alps and drains an intensely cultivated and industrialised catchment before it discharges to the Gulf of Lion. We investigated the interaction of catchment geomorphology with nitrate sources (atmosphere, agriculture, and nitrification of soil organic matter) and removal processes in large and diverse watersheds on the basis of dual nitrate isotope signatures in river water.In March 2015, we took surface water samples along the Rhône River, including its main tributaries, and measured nutrient concentrations and the stable isotopic composition of nitrate (δ15N, δ18O and Δ17O), and water (δ18O-H2O).Results show that high altitude regions are dominated by nitrate from nitrification in pristine soils and atmospheric deposition, while nitrate in the downstream Rhône River originates mainly from nitrification of agricultural/urban sources. Parallel increases in δ15N and δ18O reflect the influence of primary production. Previous studies suggested robust correlations between land use and [Formula: see text]. Based on our observation that nitrate δ15N values at higher altitudes are lower than expected, we assume that lower nitrate δ15N values likely reflect limited nitrate consumption and lower soil nitrogen turnover rates. We propose that correlation between land use and nitrate δ15N is sensitive to slope and geomorphology.


Phase-based control of the central pattern generator for locomotion.
We have previously shown that the lamprey's central pattern generator (CPG) for locomotion can be manipulated by applying electrical stimuli to the spinal cord at precise phases within the CPG cycle. Here we demonstrate how these so-called phase dependent responses (PDR) can be used to repeatably and reliably manipulate individual parameters of locomotion in the lamprey. In particular, we show that: (1) the PDR for an arbitrary stimulus prescribes the phases at which to stimulate in order to effect specific modifications of the locomotor output; (2) ipsilateral and contralateral burst lengths can be controlled separately; and (3) the responses predicted by a single-cycle PDR plot remain stable over many cycles of stimulation. All of these properties suggest that phase-dependent stimulation may be an effective means of controlling the CPG in a future spinal locomotion neuroprosthesis.


In vitro models.
The current resurgence of interest in the cancer stem cell (CSC) hypothesis as possibly providing a unifying theory of cancer biology is fueled by the growing body of work on normal adult tissue stem cells and the promise that CSC may hold the key to one of the central problems of clinical oncology: tumor recurrence. Many studies suggest that the microenvironment plays a role, perhaps a seminal one, in cancer development and progression. In addition, the possibility that the stem cell-like component of tumors is capable of rapid and reversible changes of phenotype raises questions concerning studies with these populations and the application of what we learn to the clinical situation. These types of questions are extremely difficult to study using in vivo models or freshly isolated cells. Established cell lines grown in defined conditions provide important model systems for these studies. There are three types of in vitro models for CSCs: (a) selected subpopulations of existing tumor lines (derived from serum-containing medium; (b) creation of lines from tumor or normal cells by genetic manipulation; or (c) direct in vitro selection of CSC from tumors or sorted tumor cells using defined serum-free conditions. We review the problems associated with creating and maintaining in vitro cultures of CSCs and the progress to date on the establishment of these important models.


Predictive validity of a medication adherence measure in an outpatient setting.
This study examines the psychometric properties and tests the concurrent and predictive validity of a structured, self-reported medication adherence measure in patients with hypertension. The authors also assessed various psychosocial determinants of adherence, such as knowledge, social support, satisfaction with care, and complexity of the medical regimen. A total of 1367 patients participated in the study; mean age was 52.5 years, 40.8% were male, 76.5% were black, 50.8% graduated from high school, 26% were married, and 54.1% had income <$5,000. The 8-item medication adherence scale was reliable (alpha=.83) and significantly associated with blood pressure control (P<.05). Using a cutpoint of <6, the sensitivity of the measure to identify patients with poor blood pressure control was estimated to be 93%, and the specificity was 53%. The medication adherence measure proved to be reliable, with good concurrent and predictive validity in primarily low-income, minority patients with hypertension and might function as a screening tool in outpatient settings with other patient groups.


[Trajectory modeling for estimating the trend of human papillomavirus infection status among men who have sex with men].
To investigate whether trajectory model can be used to explore the trend of anal human papillomavirus (HPV) infection status among HIV-negative men who have sex with men (MSM). HIV-negative MSM were recruited by using the "snowball" method from 1st September 2016 to 30th September 2017 in Urumqi. The subjects were followed-up every six months since enrollment. The cell samples in anal canal were collected and the 37-type HPV test kits were used for identification and classification of HPV infection at both baseline and follow-up visits. Taking the cumulative number of different types of HPV as the dependent variable and follow-up visits as the independent variable, the trajectory model was established for the study subjects who completed baseline, 6 months and 12 months follow-up. The model was used to simulate the trend of HPV infection status when the subjects were divided into 1, 2, 3 and 4 subgroups. Bayesian information criterion (BIC), log Bayes factor and average posterior probability (AvePP) were used to evaluate the fitting effect. A total of 400 HIV-negative MSM were recruited at baseline and 187 subjects completed baseline and two follow-ups. The fitting effect attained best when the variation trend was divided into two subgroups. The first subgroup accounted for 54.5%(102/187) of the total, and the curve of change in HPV infection was decreasing; the second subgroup accounted for 45.5%(85/187) of the total, and the curve of change in HPV infection was increasing. Trajectory model can effectively distinguish the trend of HPV infection status in HIV-negative MSM to identify the high-risk group of HPV infection.


Shaping the Future of Perinatal Cells: Lessons From the Past and Interpretations of the Present.
Since their discovery and characterization, mesenchymal stromal cells (MSC) have been a topic of great interest in regenerative medicine. Over the last 10 years, detailed studies investigated the properties of MSC from perinatal tissues and have indicated that these cells may represent important tools for restoring tissue damage or promoting regeneration and repair of the tissue microenvironment. At first, perinatal tissue-derived MSC drew attention due to their potential differentiation capacities suggested by their early embryological origin. It is nowadays accepted that perinatal tissue-derived MSC are promising for a wide range of regenerative medicine applications because of their unique immune modulatory properties, rather than their differentiation ability. As a matter of fact, the activation and function of various cells of the innate and adaptive immune systems are suppressed and modulated by MSC from different perinatal tissues, such as human term placenta. However, the mechanisms by which they act on immune cells to facilitate tissue repair during pathological processes remain to be thoroughly elucidated to develop safe and efficient therapeutic approaches. In addition to immune modulatory ability, several other peculiar characteristics of placenta MSC, less explored and/or more debated, are being investigated. These include an understanding of the anti-microbial properties and the role of placental MSC in tumor progression. Moreover, a thorough investigation on preparation methods, bioactive factors, mechanisms of action of the cell secretome, and the development of potency assays to predict clinical efficacy of placenta MSC and their products, are necessary to provide a solid basis for their clinical application.


Effects of Thai massage on physical fitness in soccer players.
[Purpose] The aim of this study was to determine the effects of Thai massage on physical fitness in soccer players. [Subjects and Methods] Thirty-four soccer players were randomly assigned to receive either rest (the control group) or three 30-minute sessions of Thai massage over a period of 10 days. Seven physical fitness tests consisting of sit and reach, hand grip strength, 40 yards technical agility, 50-meter sprint, sit-ups, push-ups, and VO2, max were measured before and after Thai massage or rest. [Results] All the physical fitness tests were significantly improved after a single session of Thai massage, whereas only the sit and reach, and the sit-ups tests were improved in the control group. [Conclusion] Thai massage could provide an improvement in physical performance in soccer players.


Dietary fish and evening primrose oil with vitamin E effects on semen variables in cockerels.
Our aim was to determine the effect of n-3 (2%, wt/wt, fish oil rich diet) and n-6 (2%, wt/wt, evening primrose oil rich diet) fatty acid dietary supplementation and their combination with two concentrations of vitamin E (40 vs 200 mg/kg) on semen variables and on fatty acid and vitamin E profiles of spermatozoa in broiler breeders at 32, 42 and 52 weeks of age. The inclusion of fish oil in the cockerel diets increased the docosahexaenoic acid proportion in the sperm phospholipid fraction, which was almost threefold higher compared to the other two groups irrespective of vitamin E supplementation. In contrast, an increase in the proportion of total n-6 polyunsaturates, mainly 22:4n-6, was observed in the evening primrose oil group compared to the control only when the dietary content of vitamin E was increased to 200 mg/kg. Sperm concentration was decreased in the fish and evening primrose oil groups if vitamin E was 40 mg/kg, but such an effect was prevented in the fish, not the evening primrose oil group, by increasing the vitamin E to 200 mg. The proportion of motile spermatozoa was improved by the increased supplementation of vitamin E in all oil treatments.


A survey for paramyxoviruses in caged birds, wild birds, and poultry in New Zealand.
To determine the presence of avian paramyxovirus (APMV) types 1, 2, and 3 in caged and wild birds, and APMV-2 and -3 in poultry in New Zealand. Blood samples collected from caged (231) and wild birds (522) from various regions of New Zealand in 1997-99 were tested by haemagglutination inhibition (HI) test for antibodies to APMV types 1, 2, and 3. Blood samples collected from 1778 commercial poultry in 1996-99 were tested for APMV-2 and APMV-3 antibodies and the samples that reacted with APMV-3 antigen were tested for antibodies to APMV-1. Isolation of APMV was attempted from cloacal swabs collected from 116 of the caged birds and 175 of the wild birds sampled. Antibodies to APMV types 1, 2, and 3 were detected in 4.8, 1.7, and 2.6%, respectively, of caged bird samples. The majority of these caged birds were 'exotic' or 'fancy' poultry breeds. Amongst wild birds, 4.2% had titres to APMV-2 and over half of these were passerine birds; 1.7% of the samples had titres to APMV-1 and 0.8% to APMV-3 antigen. No virus was isolated from any of the cloacal swabs tested. Of the 1778 poultry serum samples tested, only 5 reacted with APMV-3 antigen and these were later found to be cross-reactions to APMV-1. No reactions were detected with APMV-2 antigen. APMV-1 is present in caged birds, wild birds, and poultry of New Zealand. There is no conclusive evidence of the presence of APMV-2 and APMV-3 in poultry or APMV-3 in wild birds. The results do not provide conclusive evidence for the presence of APMV-2 in wild birds in New Zealand.


A study of the effects of 8-week acupuncture treatment on patients with Parkinson's disease.
Parkinson's disease (PD) is a degenerative brain disorder, resulting in decreased neural responses in the supplementary motor area, putamen, and thalamus. Previous research showed that acupuncture was able to improve the motor dysfunction. The primary aim of this study is to assess the efficacy of longer acupuncture treatment for preventing brain degeneration in patients with PD. Ten outpatients with PD were recruited from Kyung Hee Medical Hospital. Behavioral and neural responses were examined before and after 8 weeks of acupuncture treatment. A semi-individualized treatment approach was used; patients were treated for 15 minutes with 120-Hz electro-acupuncture at the right GB34 and Taechung (LR3), followed by manual acupuncture based on the individual symptoms of the patient. Immediately after 8 weeks of acupuncture treatment, the Unified Parkinson's Disease Rating Scale (UPDRS) sub-scores and the depression scores for the patients had statistically decreased compared to the scores before acupuncture treatment; moreover, 8 weeks later, these scores remained stable. Compared to the neural responses before the acupuncture stimulation, those after the acupuncture treatment were significantly higher in the thalamus, cingulate gyrus, anterior cingulate, lingual gyrus, parahippocampal gyrus, lateral globus pallidus, mammillary body, middle temporal gyrus, cuneus, and fusiform gyrus. Finally, a positive correlation was found between the UPDRS and the mean magnetic resonance signal change for the thalamus. This study found beneficial clinical effects of 8-week acupuncture treatment in the brains of patients with PD.


Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in adult and pediatric burn patients.
Burn patients are prone to infections which often necessitate broad antibiotic coverage. Vancomycin is a common antibiotic after burn injury and is administered alone (V), or in combination with imipenem-cilastin (V/IC) or piperacillin-tazobactam (V/PT). Sparse reports indicate that the combination V/PT is associated with increased renal dysfunction. The purpose of this study was to evaluate the short-term impact of the three antibiotic administration types on renal dysfunction. All pediatric and adult patients admitted to our centers between 2004 and 2016 with a burn injury were included in this retrospective review if they met the criteria of exposition to either V, V/IC, or V/PT for at least 48 h, had normal baseline creatinine, and no pre-existing renal dysfunction. Creatinine was monitored for 7 days after initial exposure; the absolute and relative increase was calculated, and patient renal outcomes were classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria depending on creatinine increases and estimated creatinine clearance. Secondary endpoints (demographic and clinical data, incidences of septicemia, and renal replacement therapy) were analyzed. Antibiotic doses were modeled in logistic and linear multivariable regression models to predict categorical KDIGO events and relative creatinine increase. Out of 1449 patients who were screened, 718 met the inclusion criteria, 246 were adults, and 472 were children. Between the study cohorts V, V/IC, and V/PT, patient characteristics at admission were comparable. V/PT administration was associated with a statistically higher serum creatinine, and lower creatinine clearance compared to patients receiving V alone or V/IC in adults and children after burn injury. The incidence of KDIGO stages 1, 2, and 3 was higher after V/PT treatment. In children, the incidence of KDIGO stage 3 following administration of V/PT was greater than after V/IC. In adults, the incidence of renal replacement therapy was higher after V/PT compared with V or V/IC. Multivariate modeling demonstrated that V/PT is an independent predictor of renal dysfunction. Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in pediatric and adult burn patients when compared to vancomycin alone or vancomycin plus imipenem-cilastin. The mechanism of this increased nephrotoxicity remains elusive and warrants further scientific evaluation.


Harmful Alcohol Use Among Patients with Tuberculosis in Gedeo Zone, Southern Ethiopia.
Alcohol consumption among patients with tuberculosis is on the rise. There is evidence that alcohol consumption negatively affects treatment outcomes for these populations. Due to this, a substantial number of people relapse, withdraw from treatment, or even die as a result of their alcohol addiction. Despite this, little research has been conducted on the factors associated with the harmful use of alcohol by this group of people in Ethiopia. The purpose of this study was to determine the prevalence and associated factors of harmful alcohol use among patients with tuberculosis in the Gedeo Zone, southern Ethiopia. A cross-sectional study was conducted at healthcare facilities. Four hundred and fifteen participants aged 18 and older were recruited using a systematic random sampling method. Data on sociodemographic factors, clinical factors, social support, perceptions of the stigma associated with tuberculosis, and depression were collected using structured and validated instruments. Measurement of harmful alcohol consumption was conducted using the AUDIT. The prevalence of harmful alcohol use among tuberculosis patients was 20% (95% CI; 16.1-24.2%). There is a significant correlation between medical comorbidity (AOR = 2.44, 95% CI: 1.29-4.62), disease duration (≥12 months) (AOR = 2.88, 95% CI: 1.03-3.04), and being male (AOR = 2.10, 95% CI: 1.17-3.77) with harmful alcohol consumption. Our study revealed that alcohol consumption was high among tuberculosis patients. The presence of comorbidities, being male, and having a long-term illness were significant predictors of harmful alcohol consumption. It is imperative to screen patients who have suffered from chronic tuberculosis for an extended period of time. It is also pertinent to screen patients with comorbid medical conditions for alcohol abuse. Screening for alcohol abuse at an early stage can prevent poor treatment outcomes as well as the effects of comorbid medical conditions and harmful use of alcohol.


A copper catalyzed azidation and peroxidation of β-naphthols via an oxidative dearomatization strategy.
Dearomatizative azidation and peroxidation of β-naphthols have been explored using copper bromide as a catalyst. These reactions lead to highly valuable naphthalenone derivatives such as quaternary azide derivatives and quaternary peroxide derivatives in good yields. This method paves an excellent way for synthesizing azides and peroxides which serve as masked surrogates for their corresponding amines and alcohols. Using this method, optically pure binol derivatives were transformed to their corresponding chiral naphthalenones in excellent yields with moderate enantioselectivity.


Effect of pH on endogenous sunlight inactivation rates of laboratory strain and wastewater sourced E. coli and enterococci.
Understanding the influence of environmental factors like pH on solar disinfection in sunlight-dependent wastewater treatment systems can aid in improving their design. Previous research found pH to influence the solar disinfection rates of bacteria in water containing exogenous photosensitizers that facilitate photo-oxidative inactivation. However, limited research has been conducted on the role of external pH on endogenous solar inactivation processes that occur independent of exogenous photosensitizers. As such, we studied the inactivation rates of laboratory-cultured and wastewater-sourced E. coli and enterococci in sensitizer-free matrices with pH ranging from 4 to 10 under full-spectrum and UVB-filtered simulated sunlight. Elevated solar inactivation rates were observed at pH 4 for all bacterial populations evaluated, and at pH 10 for laboratory-cultured and wastewater-sourced E. coli. Dark inactivation was observed at the pH extremes for some bacteria, but did not contribute significantly to the increased inactivation rates observed under simulated sunlight at these pH, except for laboratory-cultured E. coli at pH 10. UVB light was found to play an important role in sunlight inactivation, albeit the contribution of UVB light to solar inactivation observed for Enterococcus spp. diminished at pH 4 and 5, suggesting that indirect endogenous inactivation pathways facilitated by longer wavelength light were enhanced under acidic conditions. Our findings demonstrate that external pH affects the kinetics of endogenous sunlight inactivation processes, and the results have potential to be integrated into models for predicting inactivation kinetics in sunlight-mediated treatment systems that operate over a range of pH conditions.


Cardiac involvement in a large kindred with myotonic dystrophy. Quantitative assessment and relation to size of CTG repeat expansion.
To evaluate and quantitate cardiac involvement in myotonic dystrophy and assess whether the size of the trinucleotide (cytosine-thymine-guanine [CTG]) repeat expansion is a significant predictor of cardiac abnormalities. Case-control study of a large kindred with myotonic dystrophy. Ninety-one bloodline members of the kindred underwent clinical and cardiac evaluation with electrocardiograms, echocardiography (with Doppler in the majority of cases), and genetic and neurologic evaluations. Affected individuals were age-matched to normal family members. Electrocardiographic conduction abnormalities, wall motion abnormalities, mitral valve prolapse, and global parameters of systolic and diastolic function were determined by an observer blinded to all clinical data and genetic analysis. Compared with age-matched normals, patients with myotonic dystrophy (n = 25) were more likely to have conduction abnormality (52% vs 9%), mitral valve prolapse (32% vs 9%), and wall motion abnormality (28% vs 0%) (all P < .05). Left ventricular ejection fraction and stroke volume were reduced compared with normals matched for age and heart rate (P < .05), whereas Doppler indexes of diastolic function were only marginally altered. Using multivariate analysis, the number of CTG repeats (range, 69 to 1367; normal, < or = 37) was the strongest predictor of abnormalities in wall motion and electrocardiographic conduction (odds ratio of 16.5 and 5.07 per 500 repeats, respectively). The relation of mitral valve prolapse to the size of the CTG repeat was of borderline significance. Patients with more extensive neurologic findings (n = 12) had a higher incidence of wall motion and/or electrocardiographic conduction abnormalities (83% vs 43%; P = .04). Cardiac involvement in myotonic dystrophy affects predominantly the conduction system and myocardial function. Alterations in myocardial relaxation and diastolic properties, in contrast to skeletal muscle myotonia, are minor. In this kindred, the number of CTG repeats was a significant predictor of cardiac dysfunction in myotonic dystrophy.


Effect of ultrasonic degradation of hyaluronic acid extracted from rooster comb on antioxidant and antiglycation activities.
Recently, low-molecular-weight hyaluronic acid (LMWHA) has been reported to have novel features, such as free radical scavenging activities, antioxidant activities and dietary supplements. In this study, hyaluronic acid (HA) was extracted from rooster comb and LMWHA was obtained by ultrasonic degradation in order to assess their antioxidant and antiglycation activities. Molecular weight (Mw) and the content of glucuronic acid (GlcA) were used as the index for comparison of the effect of ultrasonic treatment. The effects on the structure were determined by ultraviolet (UV) spectra and Fourier transform infrared spectra (FTIR). The antioxidant activity was determined by three analytical assays (DPPH, NO and TBARS), and the inhibitory effect against glycated-BSA was also assessed. The GlcA content of HA and LMWHA was estimated at about 48.6% and 47.3%, respectively. The results demonstrate that ultrasonic irradiation decreases the Mw (1090-181 kDa) and intrinsic viscosity (1550-473 mL/g), which indicate the cleavage of the glycosidic bonds. The FTIR and UV spectra did not significantly change before and after degradation. The IC50 value of HA and LWMHA was 1.43, 0.76 and 0.36 mg/mL and 1.20, 0.89 and 0.17 mg/mL toward DPPH, NO and TBARS, respectively. Likewise LMWHA exhibited significant inhibitory effects on the AGEs formation than HA. The results demonstrated that the ultrasonic irradiation did not damage and change the chemical structure of HA after degradation; furthermore, decreasing Mw and viscosity of LMWHA after degradation may enhance the antioxidant and antiglycation activity.


Development of an Al-Based Web Diagnostic System for Phenotyping Psychiatric Disorders.
Background: Artificial intelligence (AI)-based medical diagnostic applications are on the rise. Our recent study has suggested an explainable deep neural network (EDNN) framework for identifying key structural deficits related to the pathology of schizophrenia. Here, we presented an AI-based web diagnostic system for schizophrenia under the EDNN framework with three-dimensional (3D) visualization of subjects' neuroimaging dataset. Methods: This AI-based web diagnostic system consisted of a web server and a neuroimaging diagnostic database. The web server deployed the EDNN algorithm under the Node.js environment. Feature selection and network model building were performed on the dataset obtained from two hundred schizophrenic patients and healthy controls in the Taiwan Aging and Mental Illness (TAMI) cohort. We included an independent cohort with 88 schizophrenic patients and 44 healthy controls recruited at Tri-Service General Hospital Beitou Branch for validation purposes. Results: Our AI-based web diagnostic system achieved 84.00% accuracy (89.47% sensitivity, 80.62% specificity) for gray matter (GM) and 90.22% accuracy (89.21% sensitivity, 91.23% specificity) for white matter (WM) on the TAMI cohort. For the Beitou cohort as an unseen test set, the model achieved 77.27 and 70.45% accuracy for GM and WM. Furthermore, it achieved 85.50 and 88.20% accuracy after model retraining to mitigate the effects of drift on the predictive capability. Moreover, our system visualized the identified voxels in brain atrophy in a 3D manner with patients' structural image, optimizing the evaluation process of the diagnostic results. Discussion: Together, our approach under the EDNN framework demonstrated the potential future direction of making a schizophrenia diagnosis based on structural brain imaging data. Our deep learning model is explainable, arguing for the accuracy of the key information related to the pathology of schizophrenia when using the AI-based web assessment platform. The rationale of this approach is in accordance with the Research Domain Criteria suggested by the National Institute of Mental Health.


Functional loads on freestanding and connected implants in three-unit mandibular prostheses opposing complete dentures: an in vivo study.
In vivo measurements of vertical forces and bending moments during biting and chewing were carried out on 10 three-unit prostheses in the posterior mandibles of five patients. Each patient had two prostheses, one supported by two implants and the other supported by one implant and one tooth. The results demonstrated no major difference in functional load magnitudes related to the support type. The distribution of load between the abutments was influenced more by the prosthesis geometry and implant placement than by the difference in load characteristics of tooth and implant. This conclusion, however, is limited to one implant connected to a tooth, because multiple implants form a considerably stiffer unit than do teeth. An increase in vertical load resulting from cantilever extensions on the prostheses was documented, both at bite fork measurements and during chewing. No substantial lateral bending was registered, probably because the flat occlusal surfaces and the presence of the opposing complete denture reduced lateral forces.


Reconstituted basement membrane induces glandular-like morphogenesis but no difference in ACTH synthesis of anterior pituitary cells.
Basement membrane, a thin extracellular matrix, promotes tissue integrity and differentiated phenotype. This study was performed in order to investigate the effect of basement membrane components on adrenocorticotropin (ACTH) synthesis and to observe its relationship with cell morphology. Rat anterior pituitary cells were cultured on plastic culture plate coated with either Matrigel or poly-D-lysine. Phase-contrast microscopy and scanning electron microscopy showed that cells cultured on Matrigel appeared as a three-dimensional glandular-like cell aggregate, while those cultured on plastic showed a flat, confluent monolayer. Reverse-transcription polymerase chain reaction (RT-PCR) and Northern blot analysis revealed that ACTH synthesis in the Matrigel culture was not significantly different from that in the plastic culture. Our results suggest that the relationship between the morphological changes caused by cell-substrate interaction and pituitary hormone synthesis does not exist in all pituitary cell types and that other factors associated with cell-substrate interaction influence the hormone synthesis of some pituitary cells.


Pilot Testing of Triage Coding System in Home-based Palliative Care Using Edmonton Symptom Assessment Scale.
Home-based palliative care is an essential model of palliative care that aims to provide continuity of care at patient's own home in an effective and timely manner. This study was a pilot test of triage coding system in home-based palliative care using Edmonton Symptom Assessment System (ESAS) scale. Objective of the study was to evaluate if the triage coding system in home-based palliative care: (a) Facilitated timely intervention, (b) improved symptom control, and (c) avoided hospital deaths. Homecare services were coded as high (Group 1 - ESAS scores ≥7), medium (Group 2 - ESAS scores 4-6), and low (Group 3 - ESAS scores 0-3) priority based on ESAS scores. In high priority group, patients received home visit in 0-3 working days; medium priority group, patients received home visit in 0-10 working days; and low priority group, patients received home visit in 0-15 working days. The triage duration of home visit was arbitrarily decided based on the previous retrospective audit and consensus of the experts involved in prioritization and triaging in home care. "High priority" patients were visited in 2.63 ± 0.75 days; "medium priority" patients were visited in 7.00 ± 1.5 days, and "low priority" patients were visited in 10.54 ± 2.7 days. High and medium priority groups had a statistically significant improvement in most of the ESAS symptoms following palliative home care intervention. Intergroup comparison showed that improvement in symptoms was the highest in high priority group compared to medium and low priority group. There was an 8.5% increase in home and hospice deaths following the introduction of triage coding system. There was a significant decrease in deaths in the hospital in Group 1 (6.3%) (χ (2) = 27.3, P < 0.001) compared to Group 2 (28.6%) and Group 3 (15.4%). Group 2 had more hospital deaths. Interval duration from triaging to first intervention was a significant predictor of survival with odds ratio 0.75 indicating that time taken for intervention from triaging was more significantly affecting survival than group triaging. Pilot study of testing triaging coding system in home-based palliative care showed, triage coding system: (a) Facilitated early palliative home care intervention, (b) improved symptom control, (c) decreased hospital deaths, predominantly in high priority group, and (d) time taken for intervention from triaging was a significant predictor of survival.


Effect of orthopedic implants on canine long bone compression stiffness: a combined experimental and computational approach.
Osteosynthesis for canine long bones is a complex process requiring knowledge of biology, surgical techniques and (bio)mechanical principles. Subject-specific finite element analysis constitutes a promising tool to evaluate the effect of surgical intervention on the global properties of a bone-implant construct, but suffers from a lack of validation. In this study, the biomechanical behavior of 10 canine humeri was compared before and after creation of a 10 mm bone defect stabilized with an eight-hole locking compression plate (Synthes®) and two locking screws on each fragment. The response under compression of both intact and plated samples was measured experimentally and reproduced with a finite element model. The experimental stiffness ratio between plated and intact bone was equal to 0.39 ± 0.06. A subject-specific finite element analysis including density-dependent elasto-plastic material properties for canine bone and automatic generation of orthopedic implants was then conducted to recover these experimental results. The stiffness of intact and plated samples could be predicted, with no significant differences with experimental data. The simulated stiffness ratio between plated and intact canine bone was equal to 0.43 ± 0.03. This study constitutes a first step toward the building of a virtual database of pre-computed cases, aiming at helping the veterinary surgeons to make decisions regarding the most suited orthopedic solution for a given dog and a given fracture.


A radiological analysis of lateral ligament injuries of the ankle.
Patients who presented within 5 days of an inversion injury to the ankle joint, were clinically selected for early radiological investigation and diagnosis of rupture of the lateral ligament of the ankle. Stress tenography was performed in 142 cases, and normal ranges for talar tilt and anterior draws were established in 216 normal ankles. In addition 38 cadaveric ankles were examined by peroneal tenography. No normal connection between the tendon sheath and the ankle joint was demonstrated. Sixty-five patients had positive peroneal tenograms; nine of these were positive only after manipulation. No complications occurred. Surgery was performed on 20 patients and demonstrated that common peroneal tenography was 95% accurate in diagnosing rupture of the calcaneo-fibular ligament. Of the 19 patients with proven calcaneo-fibular ligament rupture, six had a positive anterior draw sign, and nine had talar tilt. In this series both the talar tilt and anterior draw signs were found to be inaccurate. Common peroneal tenography is recommended as the method of choice for demonstrating acute rupture of the calcaneo-fibular component of the lateral ligament.


Gene expression and metabolic response of bovine oviduct epithelial cells to the early embryo.
During its journey through the oviduct, the bovine embryo may induce transcriptomic and metabolic responses, via direct or indirect contact, from bovine oviduct epithelial cells (BOECs). An in vitro model using polyester mesh was established, allowing the study of the local contact during 48 h between a BOEC monolayer and early embryos (2- or 8-cell stage) or their respective conditioned media (CM). The transcriptomic response of BOEC to early embryos was assessed by analyzing the transcript abundance of SMAD6, TDGF1, ROCK1, ROCK2, SOCS3, PRELP and AGR3 selected from previous in vivo studies and GPX4, NFE2L2, SCN9A, EPSTI1 and IGFBP3 selected from in vitro studies. Moreover, metabolic analyses were performed on the media obtained from the co-culture. Results revealed that presence of early embryos or their CM altered the BOEC expression of NFE2L2, GPX4, SMAD6, IGFBP3, ROCK2 and SCN9A. However, the response of BOEC to two-cell embryos or their CM was different from that observed to eight-cell embryos or their CM. Analysis of energy substrates and amino acids revealed that BOEC metabolism was not affected by the presence of early embryos or by their CM. Interestingly, embryo metabolism before embryo genome activation (EGA) seems to be independent of exogenous sources of energy. In conclusion, this study confirms that early embryos affect BOEC transcriptome and BOEC response was embryo stage specific. Moreover, embryo affects BOEC via a direct contact or via its secretions. However transcriptomic response of BOEC to the embryo did not manifest as an observable metabolic response.


Association between muscle function, cognitive state, depression symptoms and quality of life of older people: evidence from clinical practice.
Although low muscle function/strength is an important predictor of poor clinical outcome in older patients, information on its impact on mental health in clinical practice is still lacking. The aim of this report is to measure the impact of low muscle function measured by handgrip strength on mental health of older people during both acute illness and recovery. Four hundred and thirty-two randomly selected hospitalized older patients had their baseline demographic and clinical characteristics assessed within 72 h of admission, at 6 weeks and at 6 months. Low muscle strength-handgrip was defined using the European Working Group criteria. Mental health outcome measures including cognitive state, depression symptoms and quality of life were also measured. Among the 432 patients recruited, 308 (79%) had low muscle strength at baseline. Corresponding figures at 6 weeks and at 6 months were 140 (73%) and 158 (75%). Patients with poor muscle strength were significantly older with increased disability and poor nutritional status compared with those with normal muscle strength. After adjustment for age, gender, disability, comorbidity including severity of acute illness and body mass index patients with low muscle strength had worse cognitive function, quality of life and higher depression symptoms compared with those with normal muscle strength over a 6-month period (p < 0.05). Poor muscle strength in older people is associated with poor cognitive state and quality of life and increased depression symptoms during both acute illness and recovery.


Convolution-Based Model-Solving Method for Three-Dimensional, Unsteady, Partial Differential Equations.
Neural networks are increasingly used widely in the solution of partial differential equations (PDEs). This letter proposes 3D-PDE-Net to solve the three-dimensional PDE. We give a mathematical derivation of a three-dimensional convolution kernel that can approximate any order differential operator within the range of expressing ability and then conduct 3D-PDE-Net based on this theory. An optimum network is obtained by minimizing the normalized mean square error (NMSE) of training data, and L-BFGS is the optimized algorithm of second-order precision. Numerical experimental results show that 3D-PDE-Net can achieve the solution with good accuracy using few training samples, and it is of highly significant in solving linear and nonlinear unsteady PDEs.


Characterization of a structural intermediate of flavivirus membrane fusion.
Viral membrane fusion proceeds through a sequence of steps that are driven by triggered conformational changes of viral envelope glycoproteins, so-called fusion proteins. Although high-resolution structural snapshots of viral fusion proteins in their prefusion and postfusion conformations are available, it has been difficult to define intermediate structures of the fusion pathway because of their transient nature. Flaviviruses possess a class II viral fusion protein (E) mediating fusion at acidic pH that is converted from a dimer to a trimer with a hairpin-like structure during the fusion process. Here we show for tick-borne encephalitis virus that exposure of virions to alkaline instead of acidic pH traps the particles in an intermediate conformation in which the E dimers dissociate and interact with target membranes via the fusion peptide without proceeding to the merger of the membranes. Further treatment to low pH, however, leads to fusion, suggesting that these monomers correspond to an as-yet-elusive intermediate required to convert the prefusion dimer into the postfusion trimer. Thus, the use of nonphysiological conditions allows a dissection of the flavivirus fusion process and the identification of two separate steps, in which membrane insertion of multiple copies of E monomers precedes the formation of hairpin-like trimers. This sequence of events provides important new insights for understanding the dynamic process of viral membrane fusion.


Enhanced transduction and replication of RGD-fiber modified adenovirus in primary T cells.
Adenoviruses are often used as vehicles to mediate gene delivery for therapeutic purposes, but their research scope in hematological cells remains limited due to a narrow choice of host cells that express the adenoviral receptor (CAR). T cells, which are attractive targets for gene therapy of numerous diseases, remain resistant to adenoviral infection because of the absence of CAR expression. Here, we demonstrate that this resistance can be overcome when murine or human T cells are transduced with an adenovirus incorporating the RGD-fiber modification (Ad-RGD). A luciferase-expressing replication-deficient Ad-RGD infected 3-fold higher number of activated primary T cells than an adenovirus lacking the RGD-fiber modification in vitro. Infection with replication-competent Ad-RGD virus also caused increased cell cycling, higher E1A copy number and enriched hexon antigen expression in both human and murine T cells. Transduction with oncolytic Ad-RGD also resulted in higher titers of progeny virus and enhanced the killing of T cells. In vivo, 35-45% of splenic T cells were transduced by Ad-RGD. Collectively, our results prove that a fiber modified Ad-RGD successfully transduces and replicates in primary T cells of both murine and human origin.


Force Myography-Based Human Robot Interactions via Deep Domain Adaptation and Generalization.
Estimating applied force using force myography (FMG) technique can be effective in human-robot interactions (HRI) using data-driven models. A model predicts well when adequate training and evaluation are observed in same session, which is sometimes time consuming and impractical. In real scenarios, a pretrained transfer learning model predicting forces quickly once fine-tuned to target distribution would be a favorable choice and hence needs to be examined. Therefore, in this study a unified supervised FMG-based deep transfer learner (SFMG-DTL) model using CNN architecture was pretrained with multiple sessions FMG source data (Ds, Ts) and evaluated in estimating forces in separate target domains (Dt, Tt) via supervised domain adaptation (SDA) and supervised domain generalization (SDG). For SDA, case (i) intra-subject evaluation (Ds ≠ Dt-SDA, Ts ≈ Tt-SDA) was examined, while for SDG, case (ii) cross-subject evaluation (Ds ≠ Dt-SDG, Ts ≠ Tt-SDG) was examined. Fine tuning with few "target training data" calibrated the model effectively towards target adaptation. The proposed SFMG-DTL model performed better with higher estimation accuracies and lower errors (R2 ≥ 88%, NRMSE ≤ 0.6) in both cases. These results reveal that interactive force estimations via transfer learning will improve daily HRI experiences where "target training data" is limited, or faster adaptation is required.


Identification of endogenous HLA-A2-restricted reactivity against shared melanoma antigens in patients using the quantitative real-time polymerase chain reaction.
This study was conducted to determine whether reactivity to melanoma cells of pretreatment peripheral blood mononuclear cells (PBMCs) from patients with metastatic melanoma correlated with subsequent response to treatment with interleukin-2 (IL-2). The sensitivity of the quantitative real-time polymerase chain reaction (PCR) assay was optimized, including the total number of cells used (3 x 10(6) in 1 mL), the responder-to-stimulator cell ratio (5:1), the optimal time to incubate PBMCs with tumor (2 h), the appropriate tumor stimulators (melanoma cell lines differing only in the expression of histocompatibility leukocyte antigen [HLA-A2]), the duration of recovery in the culture of PBMCs after cryopreservation (18-24 h), and the medium used (Iscove, 10% human AB serum). Using this optimized assay to detect HLA-A2-restricted antitumor reactivity in the pretreatment PBMCs from patients with melanoma, positive reactive responses were detected in 7 of 28 patients with an objective clinical response to IL-2 therapy compared with 6 of 21 positive reactive responses in nonresponding patients. None of 12 healthy donors were positive in this study. Thus, there was no significant difference in the reactivity of pretreatment PBMCs when responders were compared with nonresponders, although the melanoma patients had an increased incidence of response compared with healthy donors (p = 0.05). The PBMCs from 11 of the 13 melanoma patients with pretreatment HLA-A2-restricted antimelanoma reactivity were tested against a panel of transfectants expressing known shared melanoma antigens. Anti-MART-1 reactivity was detected in the pretreatment PBMCs of three patients. It thus appears that some melanoma patients are immunologically primed to antigens expressed on the tumor surface, although the HLA-A2-restricted antimelanoma activity detected in this real-time PCR assay was not predictive of patients' responses to IL-2 therapy.


Rank-ordered filter for edge enhancement of cellular images using interval type II fuzzy set.
An edge-enhancement technique using an interval type II fuzzy set that uses rank-ordered filter to enhance the edges of cellular images is proposed. When cellular images from any laboratory are digitized, scanned, and stored, some kind of degradation occurs, and directly using a rank-ordered filter may not produce clear edges. These images contain uncertainties, present in edges or boundaries of the image. Fuzzy sets that take into account these uncertainties may be a good tool to process these images. However, a fuzzy set sometimes does not produce better results. We used an interval type II fuzzy set, which considers the uncertainty in a different way. It considers the membership function in the fuzzy set as "fuzzy," so the membership values lie within an interval range. A type II fuzzy set has upper and lower membership levels, and with the two levels, a new membership function is computed using Hamacher t-conorm. A new fuzzy image is formed. A rank-ordered filter is applied to the image to obtain an edge-enhanced image. The proposed method is compared with the existing methods visually and quantitatively using entropic method. Entropy of the proposed method is higher (0.4418) than the morphology method (0.2275), crisp method (0.3599), and Sobel method (0.2669), implying that the proposed method is better.


Risk of introduction of Lumpy Skin Disease into France through imports of cattle.
The lumpy skin disease (LSD) virus belongs to the genus Capripoxvirus and causes a disease in cattle with economic impacts. In November 2014, the disease was first reported in Europe (in Cyprus); it was then reported in Greece (in August 2015) and has spread through different Balkan countries since 2016. Although vector transmission is predominant in at-risk areas, long-distance transmission usually occurs through movements of infected cattle. In order to estimate the threat for France, a quantitative import risk analysis (QIRA) model was developed to assess the risk of LSD being introduced into France by imports of cattle. Based on available information and using a stochastic model, the probability of a first outbreak of LSD in France following the import of batches of infected live cattle for breeding or fattening was estimated to be 5.4 × 10-4 (95% probability interval [PI]: 0.4 × 10-4 ; 28.7 × 10-4 ) in summer months (during high vector activity) and 1.8 × 10-4 (95% PI: 0.14 × 10-4 ; 15 × 10-4 ) in winter months. The development of a stochastic QIRA made it possible to quantify the risk of LSD being introduced into France through imports of live cattle. This tool is of prime importance because the LSD situation in the Balkans is continuously changing. Indeed, this model can be updated to process new information on the changing health situation in addition to new data from the TRAde Control and Expert System (TRACES, EU database). This model is easy to adapt to different countries and to other diseases.


Molecular pathways associated with blood pressure and hexadecanedioate levels.
The dicarboxylic acid hexadecanedioate is associated with increased blood pressure (BP) and mortality in humans and feeding it to rats raises BP. Here we aim to characterise the molecular pathways that influence levels of hexadecanedioate linked to BP regulation, using genetic and transcriptomic studies. The top associations for hexadecanedioate in a genome-wide association scan (GWAS) conducted on 6447 individuals from the TwinsUK and KORA cohorts were tested for association with BP and hypertension in the International Consortium for BP and in a GWAS of BP extremes. Transcriptomic analyses correlating hexadecanedioate with gene expression levels in adipose tissue in 740 TwinsUK participants were further performed. GWAS showed 242 SNPs mapping to two independent loci achieving genome-wide significance. In rs414056 in the SCLO1B1 gene (Beta(SE) = -0.088(0.006)P = 1.65 x 10-51, P < 1 x 10-51), the allele previously associated with increased risk of statin associated myopathy is associated with higher hexadecanedioate levels. However this SNP did not show association with BP or hypertension. The top SNP in the second locus rs6663731 mapped to the intronic region of CYP4Z2P on chromosome 1 (0.045(0.007), P = 5.49x10-11). Hexadecanedioate levels also correlate with adipose tissue gene-expression of the 3 out of 4 CYP4 probes (P<0.05) and of alcohol dehydrogenase probes (Beta(SE) = 0.12(0.02); P = 6.04x10-11). High circulating levels of hexadecanedioate determine a significant effect of alcohol intake on BP (SBP: 1.12(0.34), P = 0.001; DBP: 0.70(0.22), P = 0.002), while no effect is seen in the lower hexadecanedioate level group. In conclusion, levels in fat of ADH1A, ADH1B and CYP4 encoding enzymes in the omega oxidation pathway, are correlated with hexadecanedioate levels. Hexadecanedioate appears to regulate the effect of alcohol on BP.


Inflammation, platelets, and glycoprotein IIb/IIIa inhibitors.
Atherosclerosis, with its thromboembolic complications (including sudden cardiac death, myocardial infarction, and other ischemic organ damage such as stroke and ischemic renovascular disease), represents by far the major cause of death, morbidity, and disability for industrialized countries, and is rapidly spreading worldwide. Atherosclerosis is also a paradigm for complex, multifactorial disorders that affect humans in an age-dependent fashion. Atherosclerosis has usually been studied in a descriptive framework of biological and clinical data gathered over more than a century. As such, it is a chronic inflammatory process that selectively affects arterial vessels, and is, at least in part, genetically predetermined. Despite spectacular progress in the cardiovascular discipline, with the development of therapeutic strategies that have substantially improved the outcome of affected patients, several key questions remain unanswered: Why is aging such a powerful risk for coronary artery disease? What is the triggering mechanism for atherosclerotic inflammation? Also, in the context of this and accompanying reviews, do we modify coronary inflammation with glycoprotein IIb/IIIa blockers? Recent progress in our understanding of the underlying process of atherosclerosis has provided us with the opportunity to refine the answers to some of these questions.


Effect of Mindfulness-Based Stress Reduction vs Cognitive Behavioral Therapy or Usual Care on Back Pain and Functional Limitations in Adults With Chronic Low Back Pain: A Randomized Clinical Trial.
Mindfulness-based stress reduction (MBSR) has not been rigorously evaluated for young and middle-aged adults with chronic low back pain. To evaluate the effectiveness for chronic low back pain of MBSR vs cognitive behavioral therapy (CBT) or usual care. Randomized, interviewer-blind, clinical trial in an integrated health care system in Washington State of 342 adults aged 20 to 70 years with chronic low back pain enrolled between September 2012 and April 2014 and randomly assigned to receive MBSR (n = 116), CBT (n = 113), or usual care (n = 113). CBT (training to change pain-related thoughts and behaviors) and MBSR (training in mindfulness meditation and yoga) were delivered in 8 weekly 2-hour groups. Usual care included whatever care participants received. Coprimary outcomes were the percentages of participants with clinically meaningful (≥30%) improvement from baseline in functional limitations (modified Roland Disability Questionnaire [RDQ]; range, 0-23) and in self-reported back pain bothersomeness (scale, 0-10) at 26 weeks. Outcomes were also assessed at 4, 8, and 52 weeks. There were 342 randomized participants, the mean (SD) [range] age was 49.3 (12.3) [20-70] years, 224 (65.7%) were women, mean duration of back pain was 7.3 years (range, 3 months-50 years), 123 (53.7%) attended 6 or more of the 8 sessions, 294 (86.0%) completed the study at 26 weeks, and 290 (84.8%) completed the study at 52 weeks. In intent-to-treat analyses at 26 weeks, the percentage of participants with clinically meaningful improvement on the RDQ was higher for those who received MBSR (60.5%) and CBT (57.7%) than for usual care (44.1%) (overall P = .04; relative risk [RR] for MBSR vs usual care, 1.37 [95% CI, 1.06-1.77]; RR for MBSR vs CBT, 0.95 [95% CI, 0.77-1.18]; and RR for CBT vs usual care, 1.31 [95% CI, 1.01-1.69]). The percentage of participants with clinically meaningful improvement in pain bothersomeness at 26 weeks was 43.6% in the MBSR group and 44.9% in the CBT group, vs 26.6% in the usual care group (overall P = .01; RR for MBSR vs usual care, 1.64 [95% CI, 1.15-2.34]; RR for MBSR vs CBT, 1.03 [95% CI, 0.78-1.36]; and RR for CBT vs usual care, 1.69 [95% CI, 1.18-2.41]). Findings for MBSR persisted with little change at 52 weeks for both primary outcomes. Among adults with chronic low back pain, treatment with MBSR or CBT, compared with usual care, resulted in greater improvement in back pain and functional limitations at 26 weeks, with no significant differences in outcomes between MBSR and CBT. These findings suggest that MBSR may be an effective treatment option for patients with chronic low back pain. clinicaltrials.gov Identifier: NCT01467843.


The effects of inhalation of grain dust extract and endotoxin on upper and lower airways.
To characterize the short-term effects of grain dusts on pulmonary function, mucosal inflammation, and systemic responses, four women and three men inhaled nebulized corn and soybean dust extracts, endotoxin diluted with Hanks' balanced salt solution (HBSS), and HBSS. Subjects were volunteers recruited via newspaper advertisement and were required to be healthy, nonasthmatic, nonatopic never-smokers. The mean age was 26.9 years (range, 19 to 36 years). Using a randomized, double-blind, crossover design, each subject was challenged with each of the 4 substances with at least 10 days between challenges. Serial spirometry, peripheral blood leukocyte and differential cell counts, and 24-h postchallenge nasal lavages were performed. Extracts were produced by mixing 3 g of the corn or soybean dust with 30 ml HBSS followed by shaking for 60 min, centrifugation, then filter sterilization. The endotoxin solution was produced by mixing lyophilized Escherichia coli endotoxin (serotype 0111:B4) with HBSS to attain a final concentration of 7 mg/L, which was the same as the concentration of endotoxin in both grain dust solutions. The pH of all solutions and unmixed HBSS was adjusted to 5.8, which was the native pH of the soybean dust extract. Subjects were challenged with 0.08 ml/kg of each substance, resulting in a range of endotoxin doses of 30 to 60 micrograms, similar to that which a worker might inhale over the course of one workshift. The lowest mean percentage baseline FEV1 (+/- SD) after inhalation challenge was 99.2 +/- 2.1 for HBSS, and it was significantly lower for endotoxin (90.1 +/- 8.5, p = 0.03), corn dust extract (93.1 +/- 4.3, p = 0.02), and soybean dust extract (96.2 +/- 3.7, p = 0.03). In addition, a peripheral blood leukocytosis developed after exposure to all three endotoxin-containing solutions (p < 0.05), yet a lower peripheral blood lymphocyte count was found only after inhalation of corn dust extract (p = 0.02). Interestingly, this was associated with a higher nasal lavage lymphocyte count after inhalation of corn dust extract (p = 0.03). Neither the decrease in peripheral blood lymphocytes nor the increase in nasal lymphocytes were found after inhalation of soybean dust extract or endotoxin. Our results indicate that extracts of grain dusts have physiologic effects similar to endotoxin. However, in spite of the same endotoxin levels, the effects of corn dust extract appear to have different biologic activity than either soybean dust extract or endotoxin.


Synthesis, electronic structure, and reactivity of strained nickel-, palladium-, and platinum-bridged [1]ferrocenophanes.
The group 10 bis(phosphine)metalla[1]ferrocenophanes, [{Fe(η(5)-C(5)H(4))(2)}M(Pn-Bu(3))(2)] [M = Ni (4a), Pd (4b), and Pt (4c)], have been prepared by the reaction of Li(2)[Fe(η(5)-C(5)H(4))(2)]·tmeda (5, tmeda = N,N,N',N'-tetramethylethylenediamine) with trans-[MCl(2)(Pn-Bu(3))(2)] [M = Ni (trans-6a) and Pd (trans-6b)] and cis-[PtCl(2)(Pn-Bu(3))(2)] (cis-6c), respectively. Single crystal X-ray diffraction revealed highly tilted, strained structures as characterized by α angles of 28.4° (4a), 24.5° (4b), and 25.2° (4c) and a distorted square planar environment for the group 10 metal center. UV/visible spectroscopy and cyclic voltammetry indicated that all three compounds had smaller HOMO-LUMO gaps and were more electron-rich in nature than ferrocene and other comparable [1]ferrocenophanes. DFT calculations suggested that these differences were principally due to the electron-releasing nature of the M(Pn-Bu(3))(2) metal-ligand fragments. Attempts to induce thermal or anionic ring-opening polymerization of 4a-c were unsuccessful and were complicated by, for example, competing ligand dissociation processes or unfavorable chain propagation. In contrast, these species all reacted rapidly with acids effecting clean extrusion of the bis(phosphine)metal fragment. Carbon monoxide inserted cleanly into one of the palladium-carbon bonds of 4b to afford the ring-expanded, acylated product [{Fe(η(5)-C(5)H(4))(η(5)-C(5)H(4))(CO)}Pd(Pn-Bu(3))(2)] (10). The nickel analogue 4a, however, afforded [Ni(CO)(2)(Pn-Bu(3))(2)] whereas the platinum-bridged complex 4c was inert. Remarkably, all compounds 4a-c were readily oxidized by elemental sulfur to afford the [5,5']bicyclopentadienylidene (pentafulvalene) complexes [{η(4):η(0)-C(5)H(4)(C(5)H(4))}M(Pn-Bu(3))(2)] [M = Ni (11a)] and [(η(2)-C(10)H(8))M(Pn-Bu(3))(2)] [M = Pd (11b) and Pt (11c)] by a formal 4-electron oxidation of the carbocyclic ligands. Compounds 11b and 11c represent the first examples of [5,5']bicyclopentadienylidene as a neutral η(2)-ligand. The relative energies of η(2)-coordination with respect to that of η(4):η(0) bonding were investigated for 11a-c by DFT calculations.


Development and characterization of a novel human Waldenström macroglobulinemia cell line: RPCI-WM1, Roswell Park Cancer Institute - Waldenström Macroglobulinemia 1.
Understanding the biology of Waldenström macroglobulinemia is hindered by a lack of preclinical models. We report a novel cell line, RPCI-WM1, from a patient treated for WM. The cell line secretes human immunoglobulin M (h-IgM) with κ-light chain restriction identical to the primary tumor. The cell line has a modal chromosomal number of 46 and harbors chromosomal changes such as deletion of 6q21, monoallelic deletion of 9p21 (CDKN2A), 13q14 (RB1) and 18q21 (BCL-2), with a consistent amplification of 14q32 (immunoglobulin heavy chain; IgH) identical to its founding tumor sample. The clonal relationship is confirmed by identical CDR3 length and single nucleotide polymorphisms as well as a matching IgH sequence of the cell line and founding tumor. Both also harbor a heterozygous, non-synonymous mutation at amino acid 265 in the MYD88 gene (L265P). The cell line expresses most of the cell surface markers present on the parent cells. Overall, RPCI-WM1 represents a valuable model to study Waldenström macroglobulinemia.


[Role of enkephalin-reactive system of the caudate nucleus in acquisition of alimentary conditioned reflex in dogs].
Bilateral injections of 15 and 45 mcg of synthetic analogue of TYR-D-ALA-LEY-Enkefaline-ARG into the body of the caudate nuclei in dogs produced a manifested increase in parameters of Pavlovian alimentary conditioned reflexes. Moreover, the dose of 15 mcg of LEY-enkefaline enhanced the background salivation and prolonged food consumption. Excited dogs became calm. During analogous injections into the right lateral hypothalamus the effect diminished while injections of 15 mcg of morphine hydrochloride were ineffective. The data point to role of the enkefaline-containing system in alimentary behaviour.


Development and Evaluation of the Efficacy and Toxicity of a New Hybrid Antimicrobial Peptide MY8.
Antibiotics have led to significant advancements in medicine. Unfortunately, they were faced with the emergence of pathogen resistance. According to the World Health Organization, antimicrobial resistance has been declared one of humanity's top ten global public health threats. The risk of those bacteria is not only from their being resistant to multi-antibiotics but also from their ability to form biofilms, which can be 1,000 times more resistant than planktonic bacteria. This study used rational design to hybridize two antimicrobial peptides, aiming to enhance their efficacy and stability with reduced toxicity. The MY8 novel peptide was designed from the parent peptides BMAP-27 and CAMP 211-225. Some amino acid modifications were introduced to the hybrid peptide to improve its physicochemical properties guided by several software. Its antimicrobial activity has been studied against gram-negative and gram-positive strains, which showed broad-spectrum activity with MIC values against planktonic bacteria ranging from 0.125 to 25 μM. In contrast, 25-200 μM were needed to eradicate biofilms. Moreover, the MY8 peptide showed synergism with four conventional antibiotics., It also showed reduced toxicity against mammalian cells and a slight hemolysis tendency towards erythrocytes. The design of the MY8 peptide was successful, resulting in a novel, potent, broad-spectrum antimicrobial peptide with reduced toxicity and possible synergism with conventional antibiotics.


Biosynthesis of alpha-ketoglutarate by the reductive carboxylation of succinate in Bacteroides ruminicola.
Experiments with growing cells and with cell-free extracts of Bacteroides ruminicola indicate that this anaerobic bacterium can synthesize alpha-ketoglutarate by a reductive carboxylation of succinate. When the organism was grown in medium containing succinate-1,4-(14)C, most of the radioactivity in cells was in the protein fraction and most of the (14)C in protein was in the glutamic acid family of amino acids (glutamate, proline, and arginine). When unlabeled succinate was added to culture medium containing glucose-U-(14)C, incorporation of radioactivity into the glutamic acid family of amino acids was greatly reduced. This supports the concept that succinate is an intermediate in synthesis of alpha-ketoglutarate. Cell-free extracts of the organism incubated with succinate-1,4-(14)C incorporated (14)C into amino acids and most of this was found in glutamate. The cofactors which stimulate glutamate synthesis from succinate by extracts from these cells appear to be similar to the factors that have been demonstrated with extracts from photosynthetic bacteria. The position of label in glutamate synthesized from succinate-1,4-(14)C, the probable absence of isocitric dehydrogenase, and studies with labeled citrate and with inhibitors of citric acid cycle enzymes support the concept of a reductive carboxylation of succinate as the only, or at least a major, mechanism for synthesis of alpha-ketoglutarate in this organism. This appears to be the first evidence for a net synthesis of alpha-ketoglutarate by this reaction in a nonphotosynthetic heterotrophic organism.


Genetic Diversity and Wolbachia Infection Patterns in a Globally Distributed Invasive Ant.
Understanding the phylogeographic history of an invasive species may facilitate reconstructing the history and routes of its invasion. The longhorn crazy ant, Paratrechina longicornis, is a ubiquitous agricultural and household pest throughout much of the tropics and subtropics, but little is known about the history of its spread. Here, we examine worldwide genetic variation in P. longicornis and its associated Wolbachia bacterial symbionts. Analyses of mtDNA sequences of 248 P. longicornis workers (one per colony) from 13 geographic regions reveal two highly diverged mtDNA clades that co-occur in most of the geographic regions. These two mtDNA clades are associated with different Wolbachia infection patterns, but are not congruent with patterns of nDNA (microsatellite) variation. Multilocus sequence typing reveals two distinct Wolbachia strains in P. longicornis, namely, wLonA and wLonF. The evolutionary histories of these two strains differ; wLonA appears to be primarily transmitted maternally, and patterns of mtDNA and nDNA variation and wLonA infection status are consistent with a relatively recent Wolbachia-induced selective sweep. In contrast, the observed patterns of mtDNA variation and wLonF infections suggest frequent horizontal transfer and losses of wLonF infections. The lack of nDNA structure among sampled geographic regions coupled with the finding that numerous mtDNA haplotypes are shared among regions implies that inadvertent long-distance movement through human commerce is common in P. longicornis and has shaped the genetic structure of this invasive ant worldwide.


Respiratory effects of extradural nerve block in the postoperative period.
The effects of continuous extradural block in the postoperative period on arterial hypoxaemia are discussed. Comparing two matched groups of patients following upper abdominal surgery, one receiving continuous extradural analgesia and one narcotic analgesia, there were small but statistically insignificant improvements in PaO2 in the former group. It was concluded that abdominal muscle spasm is not an important cause of postoperative arterial hypoxaemia.


Gradient silver nanoparticle layers in absorbing coatings--experimental study.
Metal island films show a characteristic absorption peak related to the surface plasmon resonance of free electrons. This kind of film can be used in absorbing coatings, together with dielectric layers. Such absorbing multilayer coatings, with and without the gradient of the silver mass thickness in metal island films throughout the coating, have been deposited by electron beam evaporation. It is shown experimentally that coatings with a gradient in the mass thickness of silver nanoparticles have higher absorption than equivalent nongradient coatings with the same total mass thickness of silver nanoparticles.