Muscarinic receptors mediate stimulation of collagen synthesis in human lung fibroblasts.
Clinical observations indicate that in chronic obstructive pulmonary disease patients, the long-acting muscarinic antagonist tiotropium delays decline in airway function, suggesting that cholinergic mechanisms contribute to long-term structural changes. Human lung fibroblasts express muscarinic receptors and the present study aimed to explore their role in controlling collagen synthesis. MRC-5, HEL-299 and primary human lung fibroblasts (phLFb) were cultured. Incorporation of [(3)H]-proline into cellular proteins was determined as measure of collagen synthesis. In MRC-5 cells, the muscarinic agonist carbachol enhanced [(3)H]-proline incorporation in a concentration-dependent manner (effective concentration of 50%: 220 nM, increase at 10 microM by 40-55%, in a different series of experiments). Likewise, 10 microM oxotremorine caused an increase of approximately 65%. For comparison, transforming growth factor-beta1 (5 ng x mL(-1)) caused an increase of approximately 80%. Effects of carbachol on total [(3)H]-proline incorporation and collagenase-sensitive [(3)H]-proline fraction were similar. The effect of 10 microM carbachol was inhibited by tiotropium (inhibitory concentration of 50%: 110 pM), prevented by pertussis toxin and the mitogen-activated protein kinase inhibitor, PD 98059. Muscarinic agonists also enhanced [(3)H]-proline incorporation in a tiotropium-sensitive manner in HEL-299 cells and phLFb. In human lung fibroblasts, muscarinic receptors exert stimulatory effects on collagen synthesis. Prolonged blockade of muscarinic-induced collagen synthesis may contribute to reported beneficial long-term effects of anticholinergics in chronic obstructive pulmonary disease.


Synthesis of Arabino glycosyl triazoles as potential inhibitors of mycobacterial cell wall biosynthesis.
A series of arabino glycosyl triazoles with varying hydrophobic groups were synthesised as putative mimics of decaprenolphosphoarabinose (DPA) as potential inhibitors of mycobacterial cell wall biosynthesis. Biological testing against Mycobacterium bovis BCG revealed low to moderate anti-mycobacterial activity, with strong dependence on the identity of the hydrophobic side chain.


Effect of gossypol on the thyroid in young rats.
The effect of gossypol on thyroid structure and function was examined. Groups of young male rats were subcutaneously injected daily with 0.2 ml gossypol acetic acid in doses of 1, 5, or 10 mg per kg body weight. Control rats were injected with vehicle only. At the end of the 15-day treatment, there was a dose-dependent decrease in the serum concentrations of thyroid hormones, i.e., free thyroxine, triiodothyronine, and reverse triiodothyronine. Histopathological examination revealed focal degeneration of thyroid follicles after a dose of 1 mg gossypol per kg body weight; widespread follicular atrophy occurred with 5 mg and 10 mg gossypol per kg body weight. The degenerating follicles were lined with discontinuous cuboidal or squamous follicular epithelium, some of which exfoliated into colloid.


How the brain resolves high conflict situations: double conflict involvement of dorsolateral prefrontal cortex.
Executive control is a human ability that allows to overcome automatic stimulus-response mappings and to act appropriate in the context of a task where the selection of relevant stimuli and the suppression of interfering information are crucial. In order to address the question which brain areas are involved in the detection and processing of two simultaneously operating sources of interference derived from a spatial incompatibility task, we used functional MRI to contrast neural activity related to a double conflict situation to single incompatibility conditions. Results show signal increase of left dorsolateral prefrontal cortex when monitoring simultaneously presented conflict. There was no additional activity in the medial prefrontal cortex or anterior cingulate cortex although these regions are expected to play an important role in all types of conflict monitoring. Further analyses of conflict resolution and post-error adaptation pointed to different underlying functional mechanisms. While the resolution of high conflict was associated with rostral ACC activation, the post-error adaptation reflecting activity during post-error trials suggests a specific medial and lateral prefrontal network which was functionally distinct from conflict-related activity. Our results also suggest a major role for the basal ganglia during error detection and resolution.


Cloning and expression of cDNA for two endogenous UV-2237 fibrosarcoma lectin genes.
cDNA libraries from the murine UV-2237-IP3 fibrosarcoma cell line were prepared in the expression vector lambda gt11. Using specific antibodies, cDNA clones coding for the 14.5-kDa and the 34.0-kDa endogenous galactoside-specific lectins were isolated. In vitro translation and immunoprecipitation of mRNAs hybrid-selected by the cloned sequences from whole cell RNA provided confirmation for the clones. RNA and DNA blot analyses revealed that the two lectin proteins represent products of two different genes. We found differential levels of the specific mRNAs when low- and high-metastatic counterparts of the UV-2237 tumor system were compared, and these genes were not expressed in detectable amounts in normal mouse liver.


Vitamin C-mediated minimisation of Rogor-induced genotoxicity.
The genotoxic effect of Rogor (an organophosphorous pesticide) at concentrations used in agriculture was studied in terms of mitotic index in onion root-tip cells, chromosome abnormalities and meiotic index in mice and lastly, lethal mutation rate in Drosophila. It was observed that the pesticide could (i) cause mitotic as well as meiotic inhibition, (ii) increase the clastogenicity rate and (iii) induce lethal mutations. The modificatory role, if any, of L-ascorbic acid (vitamin C) was studied after administering the vitamin concurrently with the pesticide. It was observed that the cytogenetic toxicity of Rogor can be appreciably minimised by vitamin C. The possible mode of antigenotoxic action of vitamin C was discussed.


The ventilator: selection of mechanical ventilators.
A comprehensive ventilator selection process can be a time-consuming and an overwhelming task. The needs assessment becomes the primary driving tool in the design of the selection process. From the needs assessment, the evaluation can be planned and organized according to the facility requirements, time constraints, and resources. The strategy can expand to an extensive project or have a succinct and condensed design. The needs assessment determines the criteria for the selection, whether it be cost, ventilator specifications, educational needs, manufacturer support needs, maintenance requirements, accessory items, or combinations of any item. Once the data have been collected, it must be analyzed and critiqued. How this examination is performed can be expansive or scaled down according to the facility's resources. Important items in the selection must be maintained and used more extensively in the decision, whereas less important items take a backseat in the operation. The final selection comes from the culmination of the entire process.


The influence of serial feeding of drinks at different temperatures on thermoregulatory responses during cycling.
In this study, we examined thermoregulatory responses to ingestion of separate aliquots of drinks at different temperatures during low-intensity exercise in conditions of moderate heat stress. Eight men cycled at 50% (s = 3) of their peak oxygen uptake (VO2peak) for 90 min (dry bulb temperature: 25.3 degrees C, s = 0.5; relative humidity: 60%, s = 5). Four 400-ml aliquots of flavoured water at 10 degrees C (cold), 37 degrees C (warm) or 50 degrees C (hot) were ingested after 30, 45, 60, and 75 min of exercise. Immediately after the 90 min of exercise, participants cycled at 95% VO2peak to exhaustion to assess exercise capacity. There were no differences between trials in rectal temperature at the end of the 90 min of exercise (cold: 38.11 degrees C, s = 0.30; warm: 38.10 degrees C, s = 0.33; hot: 38.21 degrees C, s = 0.30; P = 0.765). Mean skin temperature between 30 and 90 min tended to be influenced by drink temperature (cold: 34.49 degrees C, s = 0.64; warm: 34.53 degrees C, s = 0.69; hot: 34.71 degrees C, s = 0.48; P = 0.091). Mean heart rate from 30 to 90 min was higher in the hot trial (129 beats . min(-1), s = 7; P < 0.05) than on the cold (124 beats . min(-1), s = 9) and warm trials (126 beats . min(-1), s = 8). Ratings of thermal sensation were higher on the hot trial than on the cold trial at 35 and 50 min (P < 0.05). Exercise capacity was similar between trials (P = 0.963). The heat load and debt induced by periodic drinking resulted in similar body temperatures during low-intensity exercise in conditions of moderate heat stress due to appropriate thermoregulatory reflexes.


Modification of a human monoclonal antibody Fab fragment specific for Plasmodium falciparum 19-kDa C-terminal merozoite surface protein 1 by site-directed mutagenesis.
We recently produced human monoclonal antibody Fab fragments specific for the 19-kDa C-terminal merozoite surface protein 1 of Plasmodium falciparum in a bacterial expression system. The effect of single amino acid modifications in the third complementarity-determining regions of the heavy and light chains on affinity was examined in one of the Fab fragments, Pf25. Recombination polymerase chain reaction was used to modify Tyr(92) or Ile(97) in the light chain and Val(101) or Trp(107) in the heavy chain. No effective replacements for Tyr(92) and Val(101) were found, but possible substitutions of Ile(97) with Gly, Leu, Glu, Ala and Ser, and of Trp(107) with Arg and Ser were demonstrated. Of these modified Fab fragments, the affinities of Fabs with Ile(97)-Leu and Trp(107)-Ser mutations were slightly higher than that of the original Fab. The effects of these modifications on the antigen-antibody interaction are discussed.


Translocation, deletion/amplification, and expression of HMGIC and MDM2 in a carcinoma ex pleomorphic adenoma.
Carcinoma ex pleomorphic adenoma (CexPA) is a carcinoma developing within a pre-existing benign pleomorphic adenoma (PA). Here we describe the identification and characterization of a series of genetic events leading to translocation, deletion/amplification, and overexpression of the HMGIC and MDM2 genes in a CexPA at an early stage of development. The tumor had a pseudodiploid stemline karyotype with a del(5)(q22-23q32-33) and a t(10;12)(p15;q14-15). In addition, there were several sidelines with double minute chromosomes (dmin) or homogeneously staining regions (hsr). Fluorescence in situ hybridization (FISH) mapping revealed that the 12q14-15 breakpoint was located centromeric to HMGIC and that the entire gene was juxtaposed to the der(10) chromosome. Detailed analysis of cells with dmin and hsr revealed that HMGIC and MDM2 were deleted from the der(10) and that the dmin and hsr were strongly positive for both genes. Southern blot analysis confirmed that both HMGIC and MDM2 were amplified and that no gross rearrangements of the genes had occurred. Immunostaining revealed that the HMGIC protein was highly overexpressed particularly in the large polymorphic cells within the carcinomatous part of the tumor. These findings suggest that amplification and overexpression of HMGIC and possibly MDM2 might be important genetic events that may contribute to malignant transformation of benign PA.


A British experience of surgical voice restoration techniques as a secondary procedure following total laryngectomy.
An earlier paper (Cheesman et al., 1985) described assessment procedures for 'failed' oesophageal speakers who were referred to Charing Cross Hospital for possible Surgical Voice Restoration in 1983-4. This paper presents the results of surgical voice restoration in the first fifty laryngectomized patients referred and analyses the reasons for failure in those where surgical voice restoration was unsuccessful. 94 per cent of patients who underwent secondary voice restoration were successful at two weeks post-surgery, but this success rate dropped to 73 per cent at three months. Reasons for this are explained and the pre-requisites for a successful surgical voice restoration are indicated.


Projected Impact on Labour Productivity Costs of Cancer-Related Premature Mortality in Europe 2018-2040.
To estimate the potential cost of lost labour productivity due to cancer-related premature mortality in Europe (EU-27 plus Norway, Switzerland, Iceland and United Kingdom) from 2018 to 2040. Deaths and years of potential productive life lost due to 23 types of cancer were estimated for 2018-2040, for 31 European countries. The data were analysed by age groups, by sex and by year. Projected productivity costs were estimated by calculating gross earnings by country, gender and age group using the Human Capital Approach, adjusting for projected labour force participation and unemployment rates. Various data sources were used. Sensitivity analyses were conducted. Between 2018 and 2040, cancer is expected to cause around eight million premature deaths (58% male). The cumulative projected productivity costs in this respect are €1.3 trillion, representing an annual average of €58.7 billion, or 0.43% of the EU-27 gross domestic product. Labour productivity costs are projected to decrease by 6% from 2018 to 2040. The highest cost region is Western Europe, where Germany and France will experience the highest cumulative losses (€288 and €192 billion, respectively). The most costly cancers, in terms of total costs related to productivity losses, are of the lung and colorectum (€264.4 and €116.3 billion, respectively). In terms of average productivity cost per death, the most costly forms of cancer are Hodgkin lymphoma (€301,157) and melanoma (€260,522). The novel information presented could help national policymakers anticipate possible areas for cost savings. Action should be taken on disease prevention, on reducing mortality and on delaying the age of death due to Hodgkin lymphoma, brain cancer, leukaemia and melanoma. Furthermore, the study findings enhance our understanding of macroeconomic variables and could be useful in determining a re-allocation of health expenditures.


Electrodiagnostic approach to the patient with suspected myopathy.
Electrodiagnostic testing is a useful component of the approach to a patient with suspected myopathy. It follows the history and is guided by the neurologic examination findings. Uncovering various electrodiagnostic patterns (eg, fibrillation potentials with short-duration motor unit potentials, short-duration motor unit potentials without fibrillation potentials, myotonic discharges, and short-duration motor unit potentials with complex repetitive discharges) can lead to more targeted laboratory testing and a refined differential diagnosis. Electromyography may also be used to detect subclinical myopathy, assess disease activity, and help select a suitable muscle for biopsy.


Medicolegal lessons learned from thyroidectomy-related lawsuits: an analysis of judicial precedents in South Korea from 1998 to 2019.
Thyroid cancer is one of the most common cancers in South Korea, and thyroidectomy is still frequently performed. As new diagnostic methods have led to a significant increase in the early detection of thyroid cancer worldwide, medical disputes related to thyroid surgery are also likely to increase. The purpose of this study was to investigate the causes of medical disputes related to thyroidectomy and to identify ways to prevent unnecessary disputes and malpractice. We analyzed 35 judicial decisions involving thyroidectomy in South Korea from January 1998 to July 2019. The most common cause of lawsuits was "performance error during surgery" (n=19), especially "recurrent laryngeal nerve (RLN) injury" (n=7), of which five cases were ruled medical malpractice. For lawsuits involving misdiagnosis (n=14), five regarding fine needle aspiration cytology (FNAC) and frozen section examination were ruled malpractice. The most common malpractice related to informed consent was "lack of explanation about surgery complications" (n=10). Surgeons should follow guidelines to protect themselves from diagnostic error dispute; performing FNAC more often might also prevent lawsuits. When the courts judge the surgeon's negligence in cases of RLN injuries, whether bilateral or unilateral, it is necessary to consider fully the surgeon's efforts to prevent RLN injuries. Providing information and building trust through sufficient patient-doctor communication is crucial.


Sex hormone binding globulin capacity and postmenopausal hormone replacement therapy.
The sex hormone binding globulin (SHBG) capacity was measured in 26 normal untreated postmenopausal women and 10 postmenopausal women taking different types of hormone replacement therapy. The patients on hormone replacement therapy had significantly higher levels of SHBG than postmenopausal women (p less than 0.001) and also significantly higher levels than 52 normal ovulating women studied previously (Pogmore and Jequier, 1979; p less than 0.02). This suggests that postmenopausal women on hormone therapy are being overtreated.


Reprint of: Comparison of the Chemical Properties of Selenocysteine and Selenocystine with Their Sulfur Analogs.
Some chemical properties of cystine and cysteine have been compared with those of their selenium-containing analogs. Major differences were noted between their titration curves, pK values of 2.01, 5.24, and 9.96 were observed for the ionizations of the carboxyl, selenohydryl, and amino groups, respectively, of selenocysteine. These values are compared with a pK of 2.3 for the carboxyl group of cysteine and values in the range of 8-10 for the ionization of the sulfhydryl and amino groups. Selenocysteine is much more reactive with halo acid derivatives than is cysteine, and reacts readily with iodoacetate even at pH values much below the pK of the selenohydryl group. Selenocysteine has an apparent half-wave potential of -0.212 V compared with 0.021 V for cysteine. It is unstable to acid hydrolysis, being completely decomposed by heating at 110° in 6 n HCl. It is also more soluble in water than is cysteine.


Sternal Precautions and Prone Positioning of Infants Following Median Sternotomy: A Nationwide Survey.
To describe current practice of pediatric sternal precautions (PSPs) and prone positioning restrictions (PPRs) in infants after median sternotomy. A Web-based survey with 21 questions was developed on the basis of a review of current literature and expert consultation. Snowball sampling resulted in 68 participants well represented by profession throughout the United States. Approximately 80% of participants reported having institutional protocols for PSPs. Most common reported PSPs were no lifting at the axillae and no pulling of arms to achieve sitting. PSPs also included PPRs. The opinions of participants supported no PPRs or modified PPRs compared with strict PPRs. Types of PPRs varied across participants, with the majority of participants in favor of modified PPRs while PSPs were less varied. Research is needed to examine the effects of PSPs and PPRs in infants post-median sternotomy.


Fast cultivation and harvesting of oil-producing microalgae Ankistrodesmus falcatus var. acicularis fed with anaerobic digestion liquor via biogranulation in addition to nutrients removal.
This study examined the feasibility of cultivation and harvesting of oil-producing microalgae (i.e. Ankistrodesmus falcatus var. acicularis) via biogranulation in two identical sequencing batch reactors (SBRs) fed with synthetic anaerobic digestion liquor. Easily settled algae granules with compact structure appeared around day 90 and mature granules were obtained after 150 days' operation. The microalgae settleability was remarkably improved, signaling by the substantial decrease of sludge volume index (SVI30) from initially >3000 to 53.44 ± 3.31 mL/g, with settling velocity correspondingly increased from nearly 0 to 18.47 ± 0.23 m/h. Although the percentage of the target microalgae (Ankistrodesmus falcatus var. acicularis) decreased along with the granulation process, the biomass concentration (2-4 g/L) and biomass productivity (130-270 mg/L/d) using biogranulation were 10-20 times and 16-34 times that by the traditional suspension method. Compared to the seed microalgae cells, more extracellular polymeric substances (EPS) (162.54 ± 3.60 mg/g-mixed liquor volatile suspended solids (MLVSS)) with a higher proteins/polysaccharides ratio (7.62) were excreted from the mature algae granules. Moreover, the mature microalgae granules showed comparable nutrients removal, averagely 96% and 86% of dissolved organic carbon (DOC) and NH4+-N from the digestion liquor, respectively, reflecting its great potential for simultaneous microalgae cultivation, harvesting and wastewater treatment.


Successful controlled ovarian stimulation despite elevated hCG levels after first-trimester abortion in the context of fertility preservation.
Fertility preservation prior to gonadotoxic chemotherapy by cryopreservation of the ovarian tissue and controlled ovarian stimulation can be effective immediately after induced abortion in the first trimenon. In a reproductive endocrinology and infertility unit of a tertiary care university-based medical centre (University Hospital of Heidelberg) a 37-year-old women with breast cancer was counseled for fertility preservation. Cryopreservation of ovarian tissue, followed by ovarian stimulation for planned intracytoplasmatic sperm injection (ICSI), transvaginal oocyte aspiration and cryopreservation of fertilized eggs was performed in spite of persistently elevated human chorionic gonadotropin (hCG)-levels after induced abortion. Twenty-four fertilized oocytes with a fertilization rate of 92% were cryopreserved. Ovarian stimulation and oocyte cryopreservation can be successfully performed with good results immediately after miscarriage, despite persistent high hCG-levels.


Spontaneous Extraperitoneal Bladder Rupture Because of Chronic Appendicitis.
A 62-year-old man presented to the emergency department with an episode of syncope after 2-3 weeks of diffuse abdominal pain, now complaining of a severe increase in pain concurrent with >24 hours of no urine output. His workup showed an idiopathic extraperitoneal rupture of the bladder on computed tomography, which was handled conservatively with Foley insertion. Repeated follow-up and imaging showed no resolution or etiology over 2 months. The patient underwent exploratory laparotomy that showed an elongated appendix with a chronic tip appendicitis that had induced bladder rupture by chronic inflammatory changes. After repair, the patient had no further complaints.


Reduction of adhesion reformation after laparoscopic endometriosis surgery: a randomized trial with an oxidized regenerated cellulose absorbable barrier.
To evaluate the effectiveness of an oxidized regenerated cellulose absorbable barrier (Interceed [TC7] Absorbable Adhesion Barrier) in the reduction of adhesion reformation after laparoscopic surgery for endometriosis. Thirty-two premenopausal nonpregnant women who had severe endometriosis and complete posterior cul-de-sac obliteration and were undergoing laparoscopic surgery were randomly assigned to either surgery alone or surgery and Interceed. None of the subjects received any other treatment for adhesion prevention. Second-look laparoscopy was performed 12-14 weeks after laparoscopic surgery by an investigator blinded to the treatment, and the incidence of adhesion-free subjects was assessed. Twelve of 16 (75%) women treated with the oxidized regenerated cellulose barrier were free of adhesions, compared with two of 16 (12.5%) controls, a statistically significant difference (P < .05). The oxidized regenerated cellulose absorbable barrier significantly reduces adhesion reformation after laparoscopic surgery for endometriosis.


Lower expression of the equine maternally imprinted gene IGF2R is related to the slow proliferation of hinny embryonic fibroblast in vitro.
Proliferation of embryonic fibroblasts under the same cell culture conditions, hinny embryonic fibroblasts (HiEFs) was slower than horse embryonic fibroblast (HEFs), donkey embryonic fibroblasts (DEFs) and mule embryonic fibroblasts (MuEFs). The imprinted genes IGF2 and IGF2R are important for cell proliferation. Therefore, we investigated whether the slower proliferation of HiEFs is related to an aberrant gene expression of IGF2 or its receptors or genes influencing the expression of the IGF2 system. Real-time polymerase chain reaction, immunofluorescence and cell starving experiment in HEFs, DEFs, MuEFs and HiEFs revealed that the slower proliferation of HiEF in vitro was related to its lower expression of IGF2R (P < 0.001). Moreover, quantification of allele-specific expression and bisulfate assay confirmed that in both MuEFs and HiEFs, IGF2R had normal maternal imprinting, implying that the imprint aberrant was not involved in the lower IGF2R expression in HiEFs. The reduction of IGF2R expression in HiEFs is associated with its slower proliferation in vitro.


Antiphospholipid antibodies and recurrent pregnancy loss: correlation between the activated partial thromboplastin time and antibodies against phosphatidylserine and cardiolipin.
Concordance was determined among the presence of the lupus anticoagulant measured by prolongation of the activated partial thromboplastin time and IgG and IgM antibodies against phosphatidylserine and cardiolipin in 47 patients selected for study because of histories of recurrent spontaneous pregnancy loss and a positive test for at least one antiphospholipid antibody. Forty-five of 47 patients (96%) had a prolonged activated partial thromboplastin time, ranging from 46 to 150 seconds. Elevated levels of IgG antiphosphatidylserine antibodies and IgM antiphosphatidylserine antibodies were present in 41 (87%) and in 19 (40%) of samples, respectively. Antibodies against cardiolipin were less commonly observed; IgG anticardiolipin antibodies in only 32 (68%) of 47 samples and IgM anticardiolipin antibodies in 15 (36%) of 42 samples. Neither the level of IgG antiphosphatidylserine antibodies nor the level of IgG anticardiolipin antibodies correlated well with the degree of prolongation of coagulation in the activated partial thromboplastin time (R = 0.312, p = 0.032 for IgG antiphosphatidylserine antibodies versus activated partial thromboplastin time; R = 0.251, p = 0.088 for IgG anticardiolipin antibodies versus activated partial thromboplastin time). Concordance with the activated partial thromboplastin time, however, was observed in 41 (87%) samples for IgG antiphosphatidylserine antibodies and in only 32 (68%) samples for IgG anticardiolipin antibodies. Our conclusion is that the antiphosphatidylserine assay correlates best, although not totally, with the presence of lupus anticoagulant and that the antiphosphatidylserine assay is more sensitive than testing for anticardiolipin.


Rate of introduction of a low pathogenic avian influenza virus infection in different poultry production sectors in the Netherlands.
Targeted risk-based surveillance of poultry types (PT) with different risks of introduction of low pathogenic avian influenza virus (LPAIv) infection may improve the sensitivity of surveillance. To quantify the rate of introduction of LPAIv infections in different PT. Data from the Dutch LPAIv surveillance programme (2007-2010) were analysed using a generalised linear mixed and spatial model. Outdoor-layer, turkey, duck-breeder and meat-duck, farms had a 11, 8, 24 and 13 times higher rate of introduction of LPAIv than indoor-layer farms, respectively. Differences in the rate of introduction of LPAIv could be used to (re)design a targeted risk-based surveillance programme.


Linkage analysis in Dictyostelium discoideum using multiply marked tester strains: establishment of linkage group VII and the reassessment of earlier linkage data.
To aid linkage analysis and mapping studies in Dictyostelium discoideum, we have constructed several tester strains with easily scored mutations characterizing the six currently identified linkage groups. Use has been made of conditionally lethal mutants unable to grow upon Bacillus subtilis, and the locus of the mutation involved (bsgA) has been assigned to linkage group III. The mutation cobA1, which confers resistance to cobaltous chloride, has been assigned to a previously unidentified linkage group (VII). The temperature-sensitive growth mutation tsgC7, previously reported to define linkage group V, has been reassigned to group III, leaving linkage group V presently unmarked. The further use of genetic tester strains is described.


Evaluation of GalNAc-siRNA Conjugate Activity in Pre-clinical Animal Models with Reduced Asialoglycoprotein Receptor Expression.
The hepatocyte-specific asialoglycoprotein receptor (ASGPR) is an ideal candidate for targeted drug delivery to the liver due to its high capacity for substrate clearance from circulation together with its well-conserved expression and function across species. The development of GalNAc-siRNA conjugates, in which a synthetic triantennary N-acetylgalactosamine-based ligand is conjugated to chemically modified siRNA, has enabled efficient, ASGPR-mediated delivery to hepatocytes. To investigate the potential impact of variations in receptor expression on the efficiency of GalNAc-siRNA conjugate delivery, we evaluated the pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates in multiple pre-clinical models with reduced receptor expression. Despite greater than 50% reduction in ASGPR levels, GalNAc conjugate activity was retained, suggesting that the remaining receptor capacity was sufficient to mediate efficient uptake of potent GalNAc-siRNAs at pharmacologically relevant dose levels. Collectively, our data support a broad application of the GalNAc-siRNA technology for hepatic targeting, including disease states where ASGPR expression may be reduced.


Comparative evaluation of p5+14 with SAP and peptide p5 by dual-energy SPECT imaging of mice with AA amyloidosis.
Amyloidosis is a protein-misfolding disorder characterized by the extracellular deposition of amyloid, a complex matrix composed of protein fibrils, hyper-sulphated glycosaminoglycans and serum amyloid P component (SAP). Accumulation of amyloid in visceral organs results in the destruction of tissue architecture leading to organ dysfunction and failure. Early differential diagnosis and disease monitoring are critical for improving patient outcomes; thus, whole body amyloid imaging would be beneficial in this regard. Non-invasive molecular imaging of systemic amyloid is performed in Europe by using iodine-123-labelled SAP; however, this tracer is not available in the US. Therefore, we evaluated synthetic, poly-basic peptides, designated p5 and p5+14, as alternative radiotracers for detecting systemic amyloidosis. Herein, we perform a comparative effectiveness evaluation of radiolabelled peptide p5+14 with p5 and SAP, in amyloid-laden mice, using dual-energy SPECT imaging and tissue biodistribution measurements. All three radiotracers selectively bound amyloid in vivo; however, p5+14 was significantly more effective as compared to p5 in certain organs. Moreover, SAP bound principally to hepatosplenic amyloid, whereas p5+14 was broadly distributed in numerous amyloid-laden anatomic sites, including the spleen, liver, pancreas, intestines and heart. These data support clinical validation of p5+14 as an amyloid radiotracer for patients in the US.


Advection and dispersion heat transport mechanisms in the quantification of shallow geothermal resources and associated environmental impacts.
Borehole Heat Exchangers (BHEs) are increasingly being used to exploit shallow geothermal energy. This paper presents a new methodology to provide a response to the need for a regional quantification of the geothermal potential that can be extracted by BHEs and the associated environmental impacts. A set of analytical solutions facilitates accurate calculation of the heat exchange of BHEs with the ground and its environmental impacts. For the first time, advection and dispersion heat transport mechanisms and the temporal evolution from the start of operation of the BHE are taken into account in the regional estimation of shallow geothermal resources. This methodology is integrated in a GIS environment, which facilitates the management of input and output data at a regional scale. An example of the methodology's application is presented for Barcelona, in Spain. As a result of the application, it is possible to show the strengths and improvements of this methodology in the development of potential maps of low temperature geothermal energy as well as maps of environmental impacts. The minimum and maximum energy potential values for the study site are 50 and 1800 W/m(2) for a drilled depth of 100 m, proportionally to Darcy velocity. Regarding to thermal impacts, the higher the groundwater velocity and the energy potential, the higher the size of the thermal plume after 6 months of exploitation, whose length ranges from 10 to 27 m long. A sensitivity analysis was carried out in the calculation of heat exchange rate and its impacts for different scenarios and for a wide range of Darcy velocities. The results of this analysis lead to the conclusion that the consideration of dispersion effects and temporal evolution of the exploitation prevent significant differences up to a factor 2.5 in the heat exchange rate accuracy and up to several orders of magnitude in the impacts generated.


GhCIPK6a increases salt tolerance in transgenic upland cotton by involving in ROS scavenging and MAPK signaling pathways.
Salt stress is one of the most damaging abiotic stresses in production of Upland cotton (Gossypium hirsutum). Upland cotton is defined as a medium salt-tolerant crop. Salinity hinders root development, shoots growth, and reduces the fiber quality. Our previous study verified a GhCIPK6a gene response to salt stress in G. hirsutum. The homologs of GhCIPK6a were analyzed in A2 (G. arboreum), D5 (G. raimondii), and AD1 (G. hirsutum) genomes. GhCIPK6a localized to the vacuole and cell membrane. The GhCBL1-GhCIPK6a and GhCBL8-GhCIPK6a complexes localized to the nucleus and cytomembrane. Overexpression of GhCIPK6a enhanced expression levels of co-expressed genes induced by salt stress, which scavenged ROS and involved in MAPK signaling pathways verified by RNA-seq analysis. Water absorption capacity and cell membrane stability of seeds from GhCIPK6a overexpressed lines was higher than that of wild-type seeds during imbibed germination stage. The seed germination rates and seedling field emergence percentages of GhCIPK6a overexpressed lines were higher than that of control line under salt stress. Moreover, overexpressing of GhCIPK6a in cotton increased lint percentage, and fiber length uniformity under salt stress. We verified the function of GhCIPK6a by transformation and RNA-seq analysis. GhCIPK6a overexpressed lines exhibited higher tolerance to abiotic stresses, which functioned by involving in ROS scavenging and MAPK pathways. Therefore, GhCIPK6a has the potential for cotton breeding to improve stress-tolerance.


Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota.
Lubiprostone has been used to treat constipation through its effects to stimulate Cl(-) secretion, resulting in water and electrolyte secretion. Potential associated changes in intestinal mucus and the colonizing bacteria (microbiome) have not been studied. As mucus obstructions may play a role in cystic fibrosis, the hypothesis that lubiprostone alters intestinal mucus and the microbiome was investigated. Ion transport studies were performed ex vivo. For mucus and microbiome studies, mice were gavaged daily with lubiprostone or vehicle. Mucin from intestinal sections was analyzed in Carnoy's fixed tissues stained with Alcian blue. Microbiome composition was analyzed by 16S rRNA gene-based sequencing. Lubiprostone stimulated short circuit current in all mouse intestinal segments after both serosal and mucosal additions, albeit at lower concentrations in the latter. Current was Cl-dependent and blocked by mucosal diphenylcarboxylic acid, serosal bumetanide, and serosal Ba(++). The CFTR inhibitor CFTRinh172 had a marginal effect. Mucus near epithelial cells (inner layer mucus) was not present in the small intestine of any mice. Proximal colon inner mucus layer was thicker in ∆F/∆F compared with +/∆F and +/+ mice. Lubiprostone decreased inner mucus layer thickness in both proximal and distal colon of all mice. Furthermore, lubiprostone altered the intestinal microbiome by increasing abundance of Lactobacillus and Alistipes. Lubiprostone activates non-CFTR Cl(-) secretion and alters the colonic inner mucus layer, which is associated with changes in the composition of the enteric microbiome.


Increased platelet aggregation and decreased high-density lipoprotein cholesterol in women on oral contraceptives.
In vivo platelet function, serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL), and serum triglycerides (TG) were determined in 26 women starting oral contraceptives (OCA). Studies were run prior to, and after one and two months of therapy. Platelet aggregation time decreased by 50 percent or more in eight of the 26 women from a pre-experimental mean value of 387 +/- 136 seconds. TC did not vary but after the women were on medication for two months, HDL decreased from 56 +/- 14.4 mg/dl to 52 +/- 12.3 mg/dl (p less than 0.05). There was a progressive increase in TG under treatment, 74 +/- 23.3 mg/dl on the pre-experimental measurement to 93 +/- 31.0 mg/dl after two months of therapy (p less than 0.005). Women planning to use OCA might best be advised to have aggregation and serum lipid studies done before and early in usage.


Inactivation of Pseudomonas deceptionensis CM2 on chicken breasts using plasma-activated water.
The aim of this study was to examine the effectiveness of plasma-activated water (PAW) for inactivating Pseudomonas deceptionensis CM2 on chicken breasts. Sterile distilled water (SDW) was activated by gliding arc discharge plasma for 60 s, which was defined as PAW60. The chicken breast samples inoculated P. deceptionensis CM2 were dipped in PAW60 or SDW for the indicated time intervals, respectively. After the treatment of PAW60 for 12 min, the population of P. deceptionensis CM2 on chicken breast was significantly reduced by 1.05 log10 CFU/g (p < 0.05), which was higher than that of SDW-treated samples for the same time intervals (p < 0.05). The L* value of chicken breasts were increased whereas a* and b* values were decreased following PAW60 treatment, while there was no significant differences in the values of a* and b* between PAW60- and SDW-treated samples for the same time intervals (p > 0.05). As compared with SDW, PAW60 caused no significant changes in the texture characteristics (e.g. hardness, springiness, cohesiveness and gumminess) and sensory properties (e.g. appearance, color, odor, texture, acceptability). Thus, PAW can be very effective to improve microbiological safety of chicken breasts with resulting slight changes to the sensory qualities. This synergistic treatment of PAW with other non-thermal technologies should be well investigated in order to improve inactivation efficacy of PAW.


Nanomolar detection of adenosine triphosphate (ATP) using a nanostructured fluorescent chemosensing ensemble.
We report a novel nanostructured chemosensing ensemble PyNp-C13/UD, obtained by self-assembling uranine dye (UD) and an amphiphilic pyridinium salt PyNp-C13. The ensemble was developed for the fluorescence turn-on sensing of ATP in aqueous solutions and inside living cells. The assembly operates via an indicator displacement assay (IDA) method with an ultra-low detection limit of 6.8 nM.


Dynamic sampling bias and overdispersion induced by skewed offspring distributions.
Natural populations often show enhanced genetic drift consistent with a strong skew in their offspring number distribution. The skew arises because the variability of family sizes is either inherently strong or amplified by population expansions. The resulting allele-frequency fluctuations are large and, therefore, challenge standard models of population genetics, which assume sufficiently narrow offspring distributions. While the neutral dynamics backward in time can be readily analyzed using coalescent approaches, we still know little about the effect of broad offspring distributions on the forward-in-time dynamics, especially with selection. Here, we employ an asymptotic analysis combined with a scaling hypothesis to demonstrate that over-dispersed frequency trajectories emerge from the competition of conventional forces, such as selection or mutations, with an emerging time-dependent sampling bias against the minor allele. The sampling bias arises from the characteristic time-dependence of the largest sampled family size within each allelic type. Using this insight, we establish simple scaling relations for allele-frequency fluctuations, fixation probabilities, extinction times, and the site frequency spectra that arise when offspring numbers are distributed according to a power law.


The trigeminal root: an anatomical study using magnetic resonance imaging.
The trigeminal root is a remarkable structure that can be an original site of trigeminal neuralgia. However, few studies have explored the detailed anatomy of it with neuroimages. The aim of the present study was to characterize the trigeminal root using magnetic resonance (MR) imaging. Thin-sliced, axial T2-weighted imaging and coronal constructive interference in steady-state (CISS) sequence were performed for a total of 167 patients. On axial T2-weighted imaging, three divisions of the main trigeminal sensory root were unequivocally delineated in 36% of the 95 patients. Sixty-three percent of the Meckel's cave was bilaterally adjacent to the petrous portion of the internal carotid artery. On CISS sequence, course of the main trigeminal sensory root was well delineated in all of the 72 patients. The accessory sensory and motor rootlets were identified in 38% and 56% of 144 sides, respectively. Levels of the main trigeminal roots at the original site and entrance into the Meckel's as well morphology of the original segment of the main trigeminal sensory root were variable. Furthermore, in 24% of sides, three divisions of the main trigeminal sensory root were clearly delineated, arranged in variable manners. In 20% sides, segments of the superior cerebellar artery had a contact with the main trigeminal sensory root and motor rootlets. Coronal CISS sequence is useful for delineating the trigeminal root. Anatomy of the trigeminal root presents considerable inter- and intra-individual variability that can influence the symptoms of trigeminal neurovascular compression.


The beliefs, motivations, and expectations of parents who have enrolled their children in a genetic biorepository.
Little is known about parental attitudes toward return of individual research results (IRRs) in pediatric genomic research. The aim of this study was to understand the views of the parents who enrolled their children in a genomic repository in which IRRs will be returned. We conducted focus groups with parents of children with developmental disorders enrolled in the Gene Partnership (GP), a genomic research repository that offers to return IRRs, to learn about their understanding of the GP, motivations for enrolling their children, and expectations regarding the return of IRRs. Parents hoped to receive IRRs that would help them better understand their children's condition(s). They understood that this outcome was unlikely, but hoped that their children's participation in the GP would contribute to scientific knowledge. Most parents wanted to receive all IRRs about their child, even for diseases that were severe and untreatable, citing reasons of personal utility. Parents preferred electronic delivery of the results and wanted to designate their preferences regarding what information they would receive. It is important for researchers to understand participant expectations in enrolling in a research repository that offers to disclose children's IRRs in order to effectively communicate the implications to parents during the consenting process.


Synergistic effects of quercetin and vitamin E on egg production, egg quality, and immunity in aging breeder hens.
Laying hens experience a rapid decline in egg production, egg quality, and immunity, usually at the end of the peak laying period. Quercetin, a known flavonoid, exerts biological activities, including phytoestrogenic, immunity, antibiotic, antioxidant, and anti-inflammatory properties. Vitamin E also shows egg production and immunoregulatory potential in animals. This study evaluated the capacity of dietary quercetin, vitamin E, and the combination of both, to promote egg production and egg quality, and to improve the immunity of aging breeder hens. We also elucidated how quercetin and vitamin E combination could synergistically affect egg production, egg quality, and immunity in aging breeder hens. A total of 400 Tianfu broiler breeders at the age of 52 wk were randomly allotted to 4 treatments with 4 replicates, 100 hens per treatment and 25 hens per replicate. They were fed diets containing quercetin at 0.4 g/kg, Vitamin E (200 mg/kg), quercetin and vitamin E (0.4 g/kg and 200 mg/kg), and a basal diet (control) for a period 10 wk. Daily feed intake and egg production rate were recorded, and weekly records were recorded on egg quality tests. At the end of the 10-wk experimental period, blood samples and immune organ (spleen) were collected from 2 birds per replicate, totaling 32 birds. Feed intake, immune organ index, serum cytokines, and immunoglobulins were evaluated, and the mRNA expression of genes related to immunity was determined from the spleen tissue. Generally, the results showed that separately or as a combination, supplemental quercetin and vitamin E significantly improved performance and egg quality (P < 0.05), and significantly increased serum immunoglobulins (IgA, IgM, and IgG) and cytokines (IFN-γ and IL-2) concentrations, as well as promoted immune organ development and index, and promoted the expression of splenic immune-related genes (IL-2 and INF-γ) (P < 0.05), compared with the control. It was confirmed in this study that the combination of quercetin and vitamin E exert synergistic effects on egg production, egg quality, and immune function in aging hens.


Metabolism in porifera. VII. Conversion of [7,7-3H2]-fucosterol into calysterol by the sponge Calyx niceaensis.
The sponge Calyx niceaensis metabolizes administered [7,7--(3)H2]-fucosterol to produce labelled calysterol, the principal sterol component of the sponge, possessing the unique feature of a cyclopropene ring bridging C23,24.


Exercise-induced recovery of plasma lipids perturbed by ageing with nanoflow UHPLC-ESI-MS/MS.
Daily physical exercise is an essential part of life and is required for remaining healthy; it enhances therapeutic efficacy in the elderly and prevents age-related diseases associated with lipid profile alterations, such as cardiovascular disease, diabetes mellitus, and dementia. To more efficiently analyse the lipid profiles and unveil the effect of exercise in aged mice, we optimized our study by examining the effects of using ionization modifiers in the mobile phase and in-source fragmentation of lysophospholipids on the simultaneous analysis of fatty acids (FAs) including hydroxyl fatty acids, glycerophospholipids, sphingolipids, and glycerolipids using nanoflow ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry. We applied the optimization to investigate the lipidomic plasma alterations in young (7 weeks old) and aged (84 weeks old) mice (C57BL/6) subjected to treadmill exercise. Of the 390 identified lipid species, 159 were quantified to investigate ageing-related lipid species responsive to physical exercise. In particular, circulating lysophosphatidylcholine and lysophosphatidylethanolamine levels showed a significant decrease, and lysophosphatidic acid showed a simultaneous increase with ageing. The saturated FA (16:0 and 18:0) increased with ageing while the unsaturated FA 22:6 decreased. Dihydroxy fatty acid (18:1_2OH) showed an exercise-induced recovery against ageing. It is notable that the levels of five triacylglycerol species significantly increased by as much as threefold with ageing, but their levels largely recovered to those observed in the young mice after exercise. These findings can help understand the influence of ageing on lipid perturbation and the role of physical exercise on lipidomic recovery in response to ageing-associated loss of physical status. Graphical abstract.


A theory of blindsight--the anatomy of the unconscious: a proposal for the koniocellular projections and intralaminar thalamus.
This paper extends the concepts introduced by the theory of premotor relations to unconscious cognitive mechanisms. According to the theory conscious mechanisms are associated with behavioural diversity, whereas unconscious output is proposed to have an obligatory association with stereotypical behaviour. The respective processes are by definition a function of the type of reafferent motor input. Concepts of simple and complex premotor networks are introduced as a means of describing unconscious and conscious processes, respectively. Evidence shows that unconscious cognitive performance differs qualitatively from conscious mechanisms suggesting parallel processes. Although the postulated anatomical substrates for conscious and unconscious processes will function in this model as parallel segregated networks, it is proposed they are distributed throughout the same cortical areas of the brain. Motor reafference is postulated to be mediated via pallidal projections to the thalamic reticular nucleus, which is known to modulate thalamocortical pathways. The role of the koniocellular pathway of the lateral geniculate nucleus remains an enigma and has some properties in common with the well-described magnocellular and parvocellular projections. There is also much speculation about the intralaminar and midline nuclei, the so-called non-specific thalamus. The paper will examine the distinctive features of thalamocortical networks and the role of the koniocellular pathway and intralaminar nuclei (ILN) of the thalamus and suggest that they form a neuroanatomical substrate for the categorizing of unconscious cognitive processes. The ILN has unique projections back to the basal ganglia, which could serve in constraining associated neocortical networks with stereotypical behaviour and thus putative unconscious processing. Only after establishing such a theoretical framework can one hope to successfully analyze the empirical literature on the syndrome of blindsight, of which a detailed account is presented. Blindsight refers to the apparent visual abilities of patients with damage to the striate visual cortex (VI). Patients will 'guess' the shape of an object or reach towards it when presented in the blind field, in spite of denying actually seeing it, i.e., they are unconsciously aware of it. Unlike the magnocellular and parvocellular geniculate pathways the koniocellular extrastriate projections partially conserve retinal information in these patients. Could the proposed network represent an anatomical model of the Freudian subconscious?


Relationship between diffuse fibrosis assessed by CMR and depressed myocardial strain in different stages of heart failure.
To investigate the extent of the left ventricular (LV) diffuse myocardial fibrosis and the association with the degree of impaired myocardial strain in different stages of heart failure. The increased diffuse myocardial fibrosis impairs the LV systolic and diastolic function. Previous studies found that the global longitudinal strain (GLS) impacted survival in patients with heart failure with preserved ejection fraction (HFpEF). However, limited data are available regarding the association between the degree of diffuse myocardial fibrosis and the severity of impaired myocardial strain in HFpEF. Sixty-six consecutive participants with heart failure (HF), and 15 healthy controls underwent cardiac magnetic resonance (CMR) examination. T1 mapping to calculate extracellular volume fractions (ECV) were used to assess diffuse myocardial fibrosis. ECV and myocardial strains were compared among the 3 groups. Associations between these two factors were also explored. The patients with HFpEF showed increased myocardial ECV fractions (32.9 % ± 3.7 % vs. 29.2 % ± 2.9 %, p < 0.001) compared with the control group. The patients with HFm + rEF also had increased myocardial ECV fractions (36.8 % ± 5.4 % vs. 32.9 % ± 3.7 %, p < 0.001) compared with HFpEF. The myocardial ECV was significantly correlated with the GLS (r = 0.422, p = 0.020), global circumferential strain (GCS) (r = 0.491, p = 0.006), and global radial strain (GRS) (r = -0.533, p = 0.002) in the HFpEF groups, but no significant correlation was found in the HFm + rEF group (GLS: r = -0.002, p = 0.990; GCS: r = 0.153, p = 0.372; GRS: r = 0.070, p = 0.685) CONCLUSIONS: In patients with HF, only patients with HFpEF exhibited a significant correlation between increased diffuse myocardial fibrosis and impaired myocardial strain. Diffuse myocardial fibrosis plays a unique role in affecting myocardial strain in patients with HFpEF.


Molecular Pathogenesis of Myeloproliferative Neoplasms.
Myeloproliferative neoplasms (MPNs) are chronic hematological malignancies characterized by increased proliferation of MPN stem and myeloid progenitor cells with or without bone marrow fibrosis that typically lead to increased peripheral blood cell counts. The genetic and cytogenetic alterations that initiate and drive the development of MPNs have largely been defined, and we summarize these here. In recent years, advances in understanding the pathogenesis of MPNs have defined a long-preclinical phase in JAK2-mutant MPN, identified genetic loci associated with MPN predisposition and uncovered mechanistic insights in CALR-mutant MPN. The integration of molecular genetics into prognostic risk models is well-established in myelofibrosis and ongoing studies are interrogating the prognostic implications of concomitant mutations in ET and PV. Despite all these advances, the field is deficient in clonally selective therapies to effectively target the MPN clone at any stage of disease, from pre-clinical to advanced. Although the biological understanding of the pathogenesis of MPNs has progressed quickly, substantial knowledge gaps remain, including in the molecular mechanisms underlying MPN progression and myelofibrotic transformation. An ongoing goal for the MPN field is to translate advances in biological understanding to improved treatments for patients.


Quality of work life and factors associated with it among nurses in public hospitals, Iran.
There is an acute shortage of nurses worldwide including Iran. Quality of work life is important for nurses as it affects the safety and quality of care provided for patients as well as organizational factors. The aim of this study was to describe the status of quality of work life and to explore its predictors among nurses in Iran. A cross-sectional study was conducted on 2391 nurses in 85 Iranian public hospitals, selected through the convenience sampling. Data were collected using demographic information and the quality of work life questionnaires. The mean score for total quality of work life was 2.58, indicating a low level of self-reported quality of work life, with 69.3% of nurses dissatisfied with their work life. The major influencing factors were inadequate and unfair payment, lack of solving staff problems by organization and poor management support, job insecurity, high job stress, unfair promotion policies, and inadequate involvement in the decision-making. Significant predictors in the multivariate analysis for lower quality of work life were male gender, being single, older age, having lower educational levels, and working in teaching hospitals. The quality of nursing work life was at a low level and needs improvement interventions. The predictors identified allow for more targeted interventions. Nursing managers and policymakers should develop and implement successful strategies appropriately to improve the quality of work life. This includes the payments, organizational and managerial support, job security, fair promotion policies, and measures to reduce job stress.


Beyond immunity: quantifying the effects of host anti-parasite behavior on parasite transmission.
A host's first line of defense in response to the threat of parasitic infection is behavior, yet the efficacy of anti-parasite behaviors in reducing infection are rarely quantified relative to immunological defense mechanisms. Larval amphibians developing in aquatic habitats are at risk of infection from a diverse assemblage of pathogens, some of which cause substantial morbidity and mortality, suggesting that behavioral avoidance and resistance could be significant defensive strategies. To quantify the importance of anti-parasite behaviors in reducing infection, we exposed larval Pacific chorus frogs (Pseudacris regilla) to pathogenic trematodes (Ribeiroia and Echinostoma) in one of two experimental conditions: behaviorally active (unmanipulated) or behaviorally impaired (anesthetized). By quantifying both the number of successful and unsuccessful parasites, we show that host behavior reduces infection prevalence and intensity for both parasites. Anesthetized hosts were 20-39% more likely to become infected and, when infected, supported 2.8-fold more parasitic cysts. Echinostoma had a 60% lower infection success relative to the more deadly Ribeiroia and was also more vulnerable to behaviorally mediated reductions in transmission. For Ribeiroia, increases in host mass enhanced infection success, consistent with epidemiological theory, but this relationship was eroded among active hosts. Our results underscore the importance of host behavior in mitigating disease risk and suggest that, in some systems, anti-parasite behaviors can be as or more effective than immune-mediated defenses in reducing infection. Considering the severe pathologies induced by these and other pathogens of amphibians, we emphasize the value of a broader understanding of anti-parasite behaviors and how co-occurring stressors affect them.


Endothelial signals modulate hepatocyte apicobasal polarization in zebrafish.
Emerging evidence indicates that paracrine signals from endothelial cells play a role in tissue differentiation and organ formation [1-3]. Here, we identify a novel role for endothelial cells in modulating hepatocyte polarization during liver organogenesis. We find that in zebrafish, the apical domain of the hepatocytes predicts the location of the intrahepatic biliary network. The refinement of hepatocyte polarization coincides with the invasion of endothelial cells into the liver, and these endothelial cells migrate along the maturing basal surface of the hepatocytes. Using genetic, pharmacological, and transplantation experiments, we provide evidence that endothelial cells influence the polarization of the adjacent hepatocytes. This influence of endothelial cells on hepatocytes is mediated at least in part by the cell-surface protein Heart of glass and contributes to the establishment of coordinately aligned hepatocyte apical membranes and evenly spaced intrahepatic conduits.


p34cdc2 kinase-mediated release of lamins from nuclear ghosts is inhibited by cAMP-dependent protein kinase.
During mitosis the lamins are found in a hyperphosphorylated and soluble state. p34cdc2 kinase (MPF), a protein kinase complex with a pivotal role during mitosis, has been found to phosphorylate the lamins and, in some cases, though not all, to cause depolymerization of the lamina in vitro. Due to the variety of protein interactions in the lamina, there is a probable requirement for multiple enzyme activities to effect its breakdown in mitosis. Using nuclear ghosts as substrate, we have fractionated a Xenopus mitotic extract into a lamin-releasing fraction (p34cdc2 kinase) and a fraction that inhibits p34cdc2 kinase-mediated lamin release if the nuclear ghosts are first preincubated in it. The lamin-release-inhibiting activity in the p34cdc2 kinase-depleted mitotic extract is, in turn, inhibited if PKI, a protein kinase inhibitor specific for PKA, is included in the preincubation reaction mixture. Furthermore, a similar degree of inhibition can be achieved by using purified PKA to preincubate the nuclear ghosts. This suggests that dephosphorylation of PKA substrate sites is necessary for lamin depolymerization.


[Chemoinformatics study on antibacterial activity of traditional Chinese medicine compounds].
The structure-activity relationship between traditional Chinese medicine (TCM) compounds and antibacterial activity was studied by chemoinformatics approach. Cytoscape and its plug-in ChemViz were applied to compute the 2D chemical structure similarity and topological parameter TPSA (topological molecular polar surface area), which measures cell permeability of chemicals, between TCM compounds and clinical antibacterials. The overall degree of structure similarity was then calculated and represented by E-value for the eight categories of TCM compounds and the known antibacterials. Our results indicated that flavonoids showed good structural similarity with antibacterials and appropriate cell permeability, compared with those of the TCM compounds of the other categories. As flavonoids were featured by good drug safety, it suggested that they can be regarded as the preferred lead compounds skeleton structure source for further antibacterials synthesis. The application of chemoinformatics helps explore the structure-activity relationship between TCM compounds and the antibacterial activity and search for suitable antibacterial lead compounds skeleton structure source.


Photolysis and thermolysis of pyridyl carbonyl azide monolayers on single-crystal platinum.
The photochemical and thermal reactivity of a number of acyl azide-substituted pyridine compounds, namely nicotinyl azide, isonicotinyl azide, picolinyl azide and dinicotinyl azide with investigated as saturated monolayers on a single-crystal Pt(111) surface in an ultrahigh vacuum chamber. Multilayers of the substrates exhibited a maximum rate of desorption at 270 K, above which, stable saturated monolayers formed as characterized by reflection-absorption infrared spectroscopy by observation of C=O and N3 bands at 1700 cm(-1), and 2100 and 1300 cm(-1) respectively. The monolayers were stable up to 400 K. Photolysis of the monolayer (or heating above 400 K) results in the formation of the respective isocyanate intermediate after loss of nitrogen as evidenced by the appearance of a new infrared band at 2260 cm(-1) with concomitant loss of the azide bands. The resulting isocyanate saturated monolayer is stable in absence of nucleophiles, but can be quenched with appropriate nucleophiles.


A comparison of the glucocorticoid receptor system in the spinal cord and hippocampus.
Studied under in vivo conditions, uptake of [3H]corticosterone (CORT) by purified cell nuclei of the hippocampus was much higher than in the spinal cord, although the latter may contain in cytosol up to 50% of glucocorticoid receptors found in cytosol of hippocampus. Experiments were undertaken to explain these differences. First, the in vivo affinity of receptors for exogenous CORT was comparable in both tissues. Second, an inhibitor of translocation, although present, was not preferentially concentrated in the spinal cord as compared to the hippocampus. However, the sensitivity towards RNAase A, an enzyme that increased binding to DNA-cellulose (taken as a measure of increased affinity for nuclear components), was preserved in the hippocampus but absent in the cord. We discuss the possibility that refractoriness to RNAase A may play a role in the reduced nuclear uptake of [3H]CORT shown by the spinal cord in vivo, but also consider possible that heterogeneity of receptor types binding CORT in the spinal cord and hippocampus may account for the differences observed in both tissues.


Insomnia symptoms, sleep duration, and disability pensions: a prospective study of Swedish workers.
Previous studies have found insomnia and long sleep duration to be independently associated with subsequent disability pension (DP). However, the issue of a possible gender-based pattern in this context has received little attention. This study aims to assess the impact of insomnia symptoms and sleep duration on the DP rates among Swedish women and men during a 12-year follow-up period. The participants, from the general population of Malmö, Sweden, were enrolled from 1992 to 1994 (n = 4,319; participation rate 41 %), aged 45-64, healthy, and employed ≥30 h per week. Baseline inquiry data concerning psychosocial circumstances and self-reported sleep habits were compared with official register-based DP rates. Five hundred and nine persons were granted a DP. Insomnia symptoms, affirmed by 33 % of the men and 41 % of the women, were associated with receiving a DP; the hazard ratios in the fully adjusted model were 1.4 for both men [95 % confidence interval (CI) 1.1, 1.9] and women (95 % CI 1.1, 1.7). The fully adjusted hazard ratio for women sleeping ≥9 h was 7.8 (95 % CI 3.7, 16.6) for DP due to a mental disorder. In the age-adjusted analyses, the sub-domain "difficulties falling asleep" was related to DP due to mental disorders in men and DP due to cardiovascular diseases in women. The findings suggest that preventing and treating insomnia symptoms could reduce DP and that disease mechanisms linking sleep disturbances to DP may differ by gender.


Photo-patch and patch tests in patients with dermatitis over the photo-exposed areas: A study of 101 cases from a tertiary care centre in India.
Many patients with dermatitis over photo-exposed body areas are positive to many contact allergens and have a pre-existing allergic contact dermatitis. This study included patients who presented to a tertiary centre in India with dermatitis on photo-exposed body areas suspected of chronic actinic dermatitis. Their detailed histories were recorded and cutaneous and systemic examinations were performed. Patch testing was done in all the patients and photo-patch testing was carried out in 86 patients. Altogether 101 patients were included (69 males, 32 females). The most common presentation was lichenified hyperpigmented plaques on the photo-exposed sites. Photosensitivity was recorded in 64 (63%) patients and summer exacerbation in 52 (52%). Exposure to the Parthenium hysterophorus weed was recorded in 70 (69%) patients, 27 (26.7%) had a history of hair dye application and 20 (20%) had a history of atopy. Photo-patch test was positive in 11 (12.8%) patients and patch testing was positive in 71 (70%). Parthenium hysterophorus was the most common allergen implicated and was positive in three (4%) photo-patch and 52 (52%) patch tests. Other positive photo-patch test allergens were perfume mix, balsam of Peru, thiuram mix, Compositae mix and promethazine hydrochloride. Other common patch test allergens were parthenolide, colophony, fragrance mix and p-phenylenediamine (PPD) base. In the Indian population parthenium and perfume mix are the most common photoallergens in patients with dermatitis over photo-exposed areas, while parthenium, colophony, fragrance mix and PPD are the common positive allergens.


Distinct dynamical patterns that distinguish willed and forced actions.
The neural pathways for generating willed actions have been increasingly investigated since the famous pioneering work by Benjamin Libet on the nature of free will. To better understand what differentiates the brain states underlying willed and forced behaviours, we performed a study of chosen and forced actions over a binary choice scenario. Magnetoencephalography recordings were obtained from six subjects during a simple task in which the subject presses a button with the left or right finger in response to a cue that either (1) specifies the finger with which the button should be pressed or (2) instructs the subject to press a button with a finger of their own choosing. Three independent analyses were performed to investigate the dynamical patterns of neural activity supporting willed and forced behaviours during the preparatory period preceding a button press. Each analysis offered similar findings in the temporal and spatial domains and in particular, a high accuracy in the classification of single trials was obtained around 200 ms after cue presentation with an overall average of 82%. During this period, the majority of the discriminatory power comes from differential neural processes observed bilaterally in the parietal lobes, as well as some differences in occipital and temporal lobes, suggesting a contribution of these regions to willed and forced behaviours.


Gene Essentiality Is a Quantitative Property Linked to Cellular Evolvability.
Gene essentiality is typically determined by assessing the viability of the corresponding mutant cells, but this definition fails to account for the ability of cells to adaptively evolve to genetic perturbations. Here, we performed a stringent screen to assess the degree to which Saccharomyces cerevisiae cells can survive the deletion of ~1,000 individual "essential" genes and found that ~9% of these genetic perturbations could in fact be overcome by adaptive evolution. Our analyses uncovered a genome-wide gradient of gene essentiality, with certain essential cellular functions being more "evolvable" than others. Ploidy changes were prevalent among the evolved mutant strains, and aneuploidy of a specific chromosome was adaptive for a class of evolvable nucleoporin mutants. These data justify a quantitative redefinition of gene essentiality that incorporates both viability and evolvability of the corresponding mutant cells and will enable selection of therapeutic targets associated with lower risk of emergence of drug resistance.


Plasmatic cystatin C for the estimation of glomerular filtration rate in intensive care units.
To compare the sensitivity of cystatin C and creatinine in detecting decreased glomerular filtration rate. Prospective observational study. Medical intensive care unit at a university hospital. Fourteen patients hospitalised in a medical intensive care unit. Cystatin C and creatinine plasmatic levels were measured in 40 blood samples taken with an interval of at least 24 h. Glomerular filtration rate was estimated by creatinine clearance using 24-h urine collection and the classical Cockcroft-Gault equation. The ability of cystatin C to detect a glomerular filtration rate under 80 ml/min per 1.73 m(2) was significantly better than that of creatinine ( p<0.05). Cystatin C, a new plasmatic marker of renal function, could be used to detect renal failure in intensive care in the future.


Cripto-1 alters keratinocyte differentiation via blockade of transforming growth factor-beta1 signaling: role in skin carcinogenesis.
Cripto-1 is an epidermal growth factor-Cripto/FRL1/Cryptic family member that plays a role in early embryogenesis as a coreceptor for Nodal and is overexpressed in human tumors. Here we report that in the two-stage mouse skin carcinogenesis model, Cripto-1 is highly up-regulated in tumor promoter-treated normal skin and in benign papillomas. Treatment of primary mouse keratinocytes with Cripto-1 stimulated proliferation and induced expression of keratin 8 but blocked induction of the normal epidermal differentiation marker keratin 1, changes that are hallmarks of tumor progression in squamous cancer. Chemical or genetic blockade of the transforming growth factor (TGF)-beta1 signaling pathway using the ALK5 kinase inhibitor SB431542 and dominant negative TGF-beta type II receptor, respectively, had similar effects on keratinocyte differentiation. Our results show that Cripto-1 could block TGF-beta1 receptor binding, phosphorylation of Smad2 and Smad3, TGF-beta-responsive luciferase reporter activity, and TGF-beta1-mediated senescence of keratinocytes. We suggest that inhibition of TGF-beta1 by Cripto-1 may play an important role in altering the differentiation state of keratinocytes and promoting outgrowth of squamous tumors in the mouse epidermis.


GPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis.
GPRC5A functions as a lung tumour suppressor to prevent spontaneous and environmentally induced lung carcinogenesis; however, the underlying mechanism remains unclear. Here we reveal that GPRC5A at the endoplasmic reticulum (ER) membrane suppresses synthesis of the secreted or membrane-bound proteins including a number of oncogenes, the most important one being Egfr. The ER-located GPRC5A disturbs the assembly of the eIF4F-mediated translation initiation complex on the mRNA cap through directly binding to the eIF4F complex with its two middle extracellular loops. Particularly, suppression of EGFR by GPRC5A contributes significantly to preventing ionizing radiation (IR)-induced lung tumorigenesis. Thus, GPRC5A deletion enhances IR-promoted EGFR expression through an increased translation rate, thereby significantly increasing lung tumour incidence in Gprc5a(-/-) mice. Our findings indicate that under-expressed GPRC5A during lung tumorigenesis enhances any transcriptional stimulation through an active translational status, which can be used to control oncogene expression and potentially the resulting related disease.


Histamine-immunoreactive nerve fibers in the mammalian spinal cord.
New sensitive antisera against histamine were used to study the distribution of histamine-immunoreactive nerve fibers in the spinal cord of several mammalian species. Tissues were fixed with carbodiimide by transcardiac perfusion or immersion. A few immunoreactive nerve fibers were found in the cervical spinal cord of the rat in the superficial laminae of the dorsal horn, around the central canal and scattered in the anterior horn. The density of immunoreactive fibers in the cervical spinal cord of the guinea pig and tree shrew was higher, but still low. The densest networks of histamine-immunoreactive fibers were seen in the cervical spinal cord of the pig. The laminar distribution of histamine-immunoreactive fibers was similar in all species. Histamine-immunoreactive fibers were densest in lamina X, followed by laminae I-II. Scattered fibers were also seen in the white matter in the lateral and posterior funiculus in the pig. In the rat and the guinea pig, no histamine-immunoreactive cell bodies were seen in the spinal sensory ganglia. The results suggest that the histamine-immunoreactive nerve fibers in the spinal cord may originate from the brain, probably from the posterior hypothalamus, and the fiber projection is more extensive in higher mammalian species. The role of histamine in the spinal cord is not known, but it may be involved in, e.g., pain sensation.


Differential effect of adjuvant taxane-based and taxane-free chemotherapy regimens on the CK-19 mRNA-positive circulating tumour cells in patients with early breast cancer.
To determine the effect of adjuvant taxane-free and taxane-based chemotherapy regimens on the elimination of circulating tumour cells (CTCs) in patients with early breast cancer. The presence of CK-19 mRNA-positive CTCs in the peripheral blood was evaluated before and after chemotherapy, using a real-time RT-PCR assay, in a historical comparison of two cohorts of women with stage I-III breast cancer treated with adjuvant taxane-free (N=211; FE(75)C or E(75)C) and taxane-based (N=334; T/E(75)C or T/E(75)) chemotherapy. Taxane-based chemotherapy resulted in a higher incidence of CTCs' elimination than taxane-free regimens since 49.7% (74 of 149) and 33.0% (29 of 88) of patients with detectable CTCs before chemotherapy, respectively, turned negative post-chemotherapy (P=0.015). Patients treated with taxane-free regimens had a significantly lower disease-free survival (DFS) (P=0.035) than patients treated with taxane-based regimens; this difference was observed in patients with but not without detectable CTCs before chemotherapy (P=0.018 and P=0.481, respectively). The incidence of deaths was significantly higher in the taxane-free cohort of patients with but not without detectable CTCs before chemotherapy compared with that of the taxane-based cohort (P=0.002). Multivariate analysis revealed that the chemotherapy regimen was significantly associated with prolonged DFS (HR: 2.00; 95% CI=1.20-3.34). Elimination of CK-19 mRNA-positive CTCs during adjuvant chemotherapy seems to be an efficacy indicator of treatment and is associated with a favourable clinical outcome of patients with detectable CTCs before chemotherapy.


Evaluating chemical similarity as a measure to identify potential substances of very high concern.
Due to the large amount of chemical substances on the market, fast and reproducible screening is essential to prioritize chemicals for further evaluation according to highest concern. We here evaluate the performance of structural similarity models that are developed to identify potential substances of very high concern (SVHC) based on structural similarity to known SVHCs. These models were developed following a systematic analysis of the performance of 112 different similarity measures for varying SVHC-subgroups. The final models consist of the best combinations of fingerprint, similarity coefficient and similarity threshold, and suggested a high predictive performance (≥80%) on an internal dataset consisting of SVHC and non-SVHC substances. However, the application performance on an external dataset was not evaluated. Here, we evaluated the application performance of the developed similarity models with a 'pseudo-external assessment' on a set of substances (n = 60-100 for the varying SVHC-subgroups) that were putatively assessed as SVHC or non-SVHC based upon consensus scoring using expert elicitations (n = 30 experts). Expert scores were direct evaluations based on structural similarity to the most similar SVHCs according to the similarity models, and did not consider an extensive evaluation of available data. The use of expert opinions is particularly suitable as this is exactly the intended purpose of the chemical similarity models: a quick, reproducible and automated screening tool that mimics the expert judgement that is frequently applied in various screening applications. In addition, model predictions were analyzed via qualitative approaches and discussed via specific examples, to identify the model's strengths and limitations. The results indicate a good statistical performance for carcinogenic, mutagenic or reprotoxic (CMR) and endocrine disrupting (ED) substances, whereas a moderate performance was observed for (very) persistent, (very) bioaccumulative and toxic (PBT/vPvB) substances when compared to expert opinions. For the PBT/vPvB model, particularly false positive substances were identified, indicating the necessity of outcome interpretation. The developed similarity models are made available as a freely-accessible online tool. In general, the structural similarity models showed great potential for screening and prioritization purposes. The models proved to be effective in identifying groups of substances of potential concern, and could be used to identify follow-up directions for substances of potential concern.


Mycorrhizal responsiveness of maize (Zea mays L.) genotypes as related to releasing date and available P content in soil.
The aim of this study was to compare the mycorrhizal responsiveness among old and recent Chinese maize genotypes (released from 1950s to 2008) in low- and high-Olsen-P soils and to identify parameters that would indicate the relationships between the mycorrhizal responsiveness and the functional traits related to P uptake of maize. A greenhouse factorial experiment was conducted. The factors were maize genotype [Huangmaya (HMY), Zhongdan 2 (ZD2), Nongda 108 (ND108), and NE15], inoculation with or without arbuscular mycorrhizal fungi (AMF) (Rhizophagus irregularis), and Olsen-P levels (4, 9, 18, 36, or 60 mg P kg(-1)). Old and recently released genotypes differed in their response to AMF under low- and high-P supply. Three kinds of responses (in terms of shoot growth) were observed: the response was positive if the soil P content was low, but negative if the soil Olsen-P content was high (HMY and ND108); the response was neutral regardless of soil P content (ZD2); and the response was positive regardless of soil P content (NE15). Principle component (PC) analysis showed that the first PC comprised morphological and physiological traits of maize roots, and the second PC comprised mycorrhizal traits. The opposite was the case, however, in high-P soil. It is concluded that maize breeding selection from 1950s to 2000s is not always against the AM association and that AMF play positive roles in promoting the growth of some maize genotypes in high-P soil. The root length colonization by efficient AMF might be a useful parameter for breeding varieties with increased mycorrhizal responsiveness.


Acoustic structure quantification (ASQ): a new tool in sonographic examination of liver lesions in hepatic alveolar echinococcosis.
Qualitative and quantitative acoustic structure quantification (ASQ) is a new, noninvasive sonographic imaging method based on B-mode. This prospective clinical pilot study aims to answer the question whether delineation and measurement of liver lesions in hepatic alveolar echinococcosis (HAE) can be improved by ASQ. Furthermore, this is the first pilot study to explore how ASQ parameters in HAE lesions develop. A total of 24 patients (male = 13/female = 11, mean age = 52 years (16-85), mean disease duration = 68 months (1-334)) with HAE were examined with ASQ using a Toshiba Aplio 500 unit. ASQ parameters were measured in HAE liver lesions and in adjacent non-tumor parenchyma. Quantitative analysis was performed offline using ASQ quantification software. Subjectively parasitic tumors in HAE appear more prominent in color-coded ASQ imaging, but the size of lesions measured in ASQ mode does not differ from size measurements in B-mode. Median focal disturbance ratio (FD ratio) in lesions was 3 (0.1-3), compared with 0.5 (0.1-1.8) in surrounding liver parenchyma (p < 0.0001). Statistical comparison of other ASQ parameters (mode, average, standard deviation) shows results that are similarly significant with p values between p < 0.0001 and p < 0.0018. ASQ is a promising sonographic method for examination and quantification of structural changes of liver parenchyma in HAE lesions.


Morphological studies of mesothelial cells in CAPD effluent and their clinical significance.
We studied the mesothelial cells in the effluent of patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and their relationship with CAPD duration, peritoneal function, peritoneal sclerosis (PS), and sclerosing encapsulating peritonitis (SEP) in 49 patients (26 men, 23 women) treated for 3 to 161 months with CAPD. Three patients had SEP and five patients had PS. The overnight effluent was drained and centrifuged. The cell differentiation and surface area of mesothelial cells were studied by a computed light microscope system after cytospin preparation staining. The surface area of 50 cells was measured. The mesothelial cells were classified into three types according to their morphological appearance: normal cell type, with a mean surface area of 335.6+/-31.0 microm2 and mean nucleocytoplasmic ratio (N/C ratio) of 0.66+/-0.01; dyskaryotic cell type, with a mean surface area of 570.5+/-35.9 microm2 and N/C ratio 0.58+/-0.06; and giant cell type, with a mean surface area of 1,821.0+/-68.8 microm2 and N/C ratio of 0.06+/-0.01. There was a low but significant correlation between the fast peritoneal equilibration test and surface area (r=0.495; P=0.0120) and a highly significant correlation between CAPD duration and mean surface area (r=0.719; P < 0.0001). This increased cell surface area was because of both an increased surface area of normal and dyskaryotic cells and an increase in the number of dyskaryotic and giant cells. The mean surface area in patients with SEP was 709.3+/-125.4 microm2 and that in patients with PS was 586.6+/-55.2 microm2. Giant cells were found in the effluent of all three patients with SEP and three of the patients with PS. In conclusion, a marked correlation was found between the surface area of effluent mesothelial cells and the duration of CAPD. Giant cells were almost always found in the effluent of patients with SEP and PS. The surface area of mesothelial cells in the effluent might reflect morphological changes in the peritoneum during CAPD. These morphological changes and the measurement of the size of mesothelial cells may predict critical derangement of peritoneal membrane.


Lymphocyte migration in inbred Syrian hamsters with acute measles virus encephalitis.
The migratory pattern of 51Cr-labeled adult lymphocytes, as measured by 51Cr concentration in various tissues, was followed in inbred weanling Syrian hamsters infected intracranially with measles virus. Donor-labeled lymphocytes were inoculated intracardially into infected and control recipients. Increased passage of labeled lymphocytes across the blood-brain barrier was first seen on day 3 post virus inoculation and 1 day prior to development of clinical signs of acute measles encephalitis. 51Cr concentration in the brain increased progressively along with neurologic signs until the death of the hamsters. Aberration of lymphocyte migration peripherally, manifested by reduced presence of labeled cells in lymph nodes and spleen, first occurred 4 days post virus inoculation in those hamsters with clinical signs of disease. By days 5 and 6 post virus inoculation, the concentration of 51Cr in lymph nodes was 30% and 20%, respectively, of that in lymph nodes of control hamsters. Concentration of labeled lymphocytes in lymph nodes and spleen of the occasional virus-inoculated animal that appeared clinically well at time of autopsy was always greater than that in ill hamsters, and was closer to and sometimes equal to the concentration in the corresponding tissues of control hamsters. Thus, increased passage of labeled lymphocytes into the brain and decreased recovery of labeled lymphocytes in lymph nodes and spleen occurred concomitantly with increased neurologic signs of disease. No differences in presence of labeled cells in other tissues tested (liver, lung, thymus and blood) between infected and control hamsters were noted. Labeled lymphocytes from either measles virus or ovalbumin-immunized donors appeared to pass more readily into the brains of ill recipients than labeled lymphocytes from unimmunized donors.


Topologic and connectional analysis of the dorsal thalamus of Triturus alpestris (amphibia, urodela, salamandridae).
A morphological and connectional analysis was performed on the dorsal thalamus of the alpine newt, Triturus alpestris. We have used a graphic reconstruction technique for the evaluation of the connectional (HRP) data. On the basis of these reconstructions, we propose a subdivision of the salamandrid dorsal thalamus into subhabenular, anteroventral, and posterodorsal zones. Each of these zones is defined by its telencephalic projections ("ascending thalamofugal systems"). The posterodorsal zone projects to the striatum, the anteroventral zone to the pallium. The subhabenular zone projects to the subpallial telencephalon and to the tegmentum. This zonal subdivision allows a more detailed comparison of the salamandrid dorsal thalamic features with ranid dorsal thalamic structures. We compare our dorsal thalamic zones to the ones proposed by Herrick (J. Comp. Neurol. 62:239-261, '35, The Brain of the Tiger Salamander. Chicago: The University of Chicago Press, '48). Furthermore, using the same reconstructive technique, we undertook an analysis of the spatial relations of various inputs to the salamandrid dorsal thalamus ("thalamopetal systems"). Besides the well-known retinal inputs, we identified the tectum and the tegmentum as sources of inputs to the thalamus. We provide evidence that there is no extensive multi- or unimodal overlap of these thalamopetal systems.


Alexis Carrel: the good, the bad, the ugly.
It is precisely 100 years since the Nobel Prize for Physiology or Medicine was awarded to the French surgeon Alexis Carrel, the second and to date one of only five surgeons to have received this most prestigious award. In spite of his outstanding contributions to the fields of cardiovascular and transplant surgery, the anniversary of his Nobel Prize award is likely to pass unnoticed and unacknowledged because of his outspoken and well-publicized beliefs and philosophies. A review was carried out of the very many biographical papers of Carrel's work and publications. Carrel's work did indeed form the basis of modern cardio-vascular and transplant surgery. In spite of deserving the Nobel prize for his scientific work, Carrel's views on eugenics were so abhorrent that he is unlikely to ever receive the accolades he deserves.


Prognostic molecular markers in cholangiocarcinoma: a systematic review.
The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, with the incidence in United Kingdom (UK) now exceeding 1000 cases per year. It is an aggressive malignancy typified by unresponsiveness to the existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though post-operative disease recurrence is common, with 5-year survival rates of less than 25% following resection. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date, p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.


The lead contaminated land treated by the circulation-enhanced electrokinetics and phytoremediation in field scale.
Some agricultural lands have been contaminated by heavy metals in Taiwan for several decades, because the irrigation system was polluted by wastewater. In this study, a circulation-enhanced electrokinetics (CEEK) and phytoremediation were applied alternately to the real lead-contaminated site. In the beginning, the CEEK was used; then, the corn plants were raised. After this phytoremediation, the CEEK was employed again. Experimental results show that the lead concentration can be reduced from 5672 mg/kg to 2083 mg/kg (around 63%) after the three-stage treatment (CEEK + corn + CEEK). At each stage, CEEK, corn plants, and CEEK can remove around 25%, 5%, and 30% lead from the soil, respectively. During the whole process, the soil pH can maintain around neutral range and the electrical conductivity of soil was stable. The electricity consumption of the CEEK was quite low (89 USD per ton) and the corn plants still were alive throughout the remediation.


Fatal native aortic valve fungal endocarditis caused by Aspergillus flavus: A case report.
Fungal endocarditis is a rare condition, specifically in immunocompetent patients. Aspergillus species are the etiology in less than 30% of the cases. Moreover, Aspergillus flavus endocarditis is extremely rare and reported in only 7% of the total Aspergillus endocarditis cases. The most common predisposing factors are immunocompromised state, prosthetic valve, and previous cardiac surgery. In most cases, the diagnosis is delayed and occasionally missed. Prompt medical management combined with early surgical intervention is recommended once the diagnosis is established since the mortality rate is nearly 100% without surgical intervention. We report a rare and fatal case of native aortic valve endocarditis in a 49 years old diabetic patient who presented with fever and abdominal pain, complicated by multiple septic embolizations (splenic infarction, cerebral emboli, and limbs ischemia), and in which A. flavus was confirmed post mortem.


The Na-K-Cl cotransport in essential hypertension: cellular functions and genetic environment interactions.
The present paper examines factors involved in the expression of the Na-K-Cl cotransport system present in erythrocytes and in vascular cells. This transport system is modulated by vasoactive peptides such as atrial natriuretic factor and bradykinin in vascular smooth muscle and endothelial cells. The Vmax of the Na-K-Cl in human red cells displays large interindividual differences which can be mainly accounted for by genetic factors. Elevation of the Km for Na of the outward Na cotransport is found in red cells of some Caucasian hypertensives and in Black normotensives born of hypertensive parents whose blood pressure increases with salt loading. Reduction of Na intake from 200 to 10 mEq/day does not influence the activity of the cotransport in normotensive individuals but decreases the Km for Na of hypertensive subjects to values similar to those of the normotensives. These findings indicate that the Na-K-Cl cotransport is an important probe of genetic and environmental factors in the hypertensive process.


Borane Adducts of Aromatic Phosphorus Heterocycles: Synthesis, Crystallographic Characterization and Reactivity of a Phosphinine-B(C6 F5 )3 Lewis Pair.
A phosphinine-borane adduct of a Me3 Si-functionalized phosphinine and the Lewis acid B(C6 F5 )3 has been synthesized and characterized crystallographically for the first time. The reaction strongly depends on the nature of the substituents in the α-position of the phosphorus heterocycle. In contrast, the reaction of B2 H6 with various substituted phosphinines leads to an equilibrium between the starting materials and the phosphinine-borane adducts that is determined by the Lewis basicity of the phosphinine. The novel phosphinine borane adduct (6-B(C6 F5 )3 ) shows rapid and facile insertion and [4+2] cycloaddition reactivity towards phenylacetylene. A hitherto unknown dihydro-1-phosphabarrelene is formed with styrene. The reaction with an ester provides a new, facile and selective route to 1-R-phosphininium salts. These salts then undergo a [4+2] cycloaddition in the presence of Me3 Si-C≡CH and styrene to cleanly form unprecedented derivatives of 1-R-phosphabarrelenium salts.


Fluorometric study on conformational changes in the catalytic cycle of sarcoplasmic reticulum Ca(2+)-ATPase.
Changes in the fluorescence of N-acetyl-N'-(5-sulfo-1-naphthyl)ethylenediamine (EDANS), being attached to Cys-674 of sarcoplasmic reticulum Ca(2+)-ATPase without affecting the catalytic activity, as well as changes in the intrinsic tryptophan fluorescence were followed throughout the catalytic cycle by the steady-state measurements and the stopped-flow spectrofluorometry. EDANS-fluorescence changes reflect conformational changes near the ATP binding site in the cytoplasmic domain, while tryptophan-fluorescence changes most probably reflect conformational changes in or near the transmembrane domain in which the Ca2+ binding sites are located. Formation of the phosphoenzyme intermediates (EP) was also followed by the continuous flow-rapid quenching method. The kinetic analysis of EDANS-fluorescence changes and EP formation revealed that, when ATP is added to the calcium-activated enzyme, conformational changes in the ATP binding site occur in three successive reaction steps; conformational change in the calcium.enzyme.substrate complex, formation of ADP-sensitive EP, and transition of ADP-sensitive EP to ADP-insensitive EP. In contrast, the ATP-induced tryptophan-fluorescence changes occur only in the latter two steps. Thus, we conclude that conformational changes in the ATP binding site in the cytoplasmic domain are transmitted to the Ca(2+)-binding sites in the transmembrane domain in these latter two steps.


Loss of bursary 'will lead to staff cuts and debts'.
Government plans to scrap the bursary for nursing, midwifery and other health students could cost the NHS 2,000 recruits a year, a new report warns.


Differences between human and chimpanzee genomes and their implications in gene expression, protein functions and biochemical properties of the two species.
Chimpanzees are the closest living relatives of humans. The divergence between human and chimpanzee ancestors dates to approximately 6,5-7,5 million years ago. Genetic features distinguishing us from chimpanzees and making us humans are still of a great interest. After divergence of their ancestor lineages, human and chimpanzee genomes underwent multiple changes including single nucleotide substitutions, deletions and duplications of DNA fragments of different size, insertion of transposable elements and chromosomal rearrangements. Human-specific single nucleotide alterations constituted 1.23% of human DNA, whereas more extended deletions and insertions cover ~ 3% of our genome. Moreover, much higher proportion is made by differential chromosomal inversions and translocations comprising several megabase-long regions or even whole chromosomes. However, despite of extensive knowledge of structural genomic changes accompanying human evolution we still cannot identify with certainty the causative genes of human identity. Most structural gene-influential changes happened at the level of expression regulation, which in turn provoked larger alterations of interactome gene regulation networks. In this review, we summarized the available information about genetic differences between humans and chimpanzees and their potential functional impacts on differential molecular, anatomical, physiological and cognitive peculiarities of these species.