Point mutations in the DNA- and cNMP-binding domains of the homologue of the cAMP receptor protein (CRP) in Mycobacterium bovis BCG: implications for the inactivation of a global regulator and strain attenuation.
The genome of Mycobacterium tuberculosis H37Rv includes a homologue of the CRP/FNR (cAMP receptor protein/fumarate and nitrate reduction regulator) family of transcription regulators encoded by Rv3676. Sequencing of the orthologous gene from attenuated Mycobacterium bovis Bacille Calmette-Guérin (BCG) strains revealed point mutations that affect the putative DNA-binding and cNMP-binding domains of the encoded protein. These mutations are not present in the published sequences of the Rv3676 orthologues in M. bovis, M. tuberculosis or Mycobacterium leprae. An Escherichia coli lacZ reporter system was used to show that the M. tuberculosis Rv3676 protein binds to DNA sites for CRP, but this DNA binding was decreased or abolished with the Rv3676 protein counterparts from BCG strains. The DNA-binding ability of the M. tuberculosis Rv3676 protein was decreased by the introduction of base changes corresponding to the BCG point mutations. Conversely, the DNA binding of the BCG Rv3676 proteins from BCG strains was restored by removing the mutations. These data show that in this reporter system the point mutations present in the Rv3676 orthologue in BCG strains render its function defective (early strains) or abolished (late strains) and suggest that this protein might be naturally defective in M. bovis BCG strains. This raises the possibility that a contributing factor to the attenuation of BCG strains may be an inability of this global regulator to control the expression of genes required for in vivo survival and persistence.


Limitations in the use of median frequency for lung sound analysis.
The aim of this paper is to investigate methods of standardizing lung sound analysis, with a view to supplementing traditional spirometric air flow measurements to help in the diagnosis of asthma and to provide a measure of the effectiveness of treatment. Lung sounds were measured in nine patients with asthma and five control subjects, alongside air flow measurements of forced expiratory volume (FEV1) and forced vital capacity (FVC). The patients were administered the bronchodilator, salbutamol, to assess how effective these measurement techniques were for quantifying its effect. The results agree with previous studies, that analysis of lung sounds is a potentially useful tool for indicating air flow changes. The results, however, also demonstrate that the emerging standard of 'F50' or 'median frequency' should be treated with great caution because of its high sensitivity to the measurement frequency range. F50 is very unlikely to provide a reliable single indicator of lung condition.


The effect of punishment and feedback on correcting erroneous behavior.
Understanding the consequences of non-punitive sanctions and feedback for nonintentional deviations (i.e., errors) is important to effective safety policy. This study aims to address a lack of research on the effects of punishment and feedback on correcting erroneous behavior in the context of multitasking. A Multi-Attribute Task Battery (MATB-II) was employed to simulate the demands of aviating, an important area of applied safety. Sixty participants were randomly assigned to one of four experimental groups (no intervention, punishment, feedback, punishment + feedback) and asked to perform the MATB-II. Punishment, feedback, and punishment + feedback decreased error and increased performance, with punishment alone having the greatest effect. The results highlight the need for behavioral consequences or feedback to reduce erroneous behavior. From an applied perspective, these results have implications for policy and training.


Leukotriene antagonist FPL 57231 prevents the acute pulmonary effects of Escherichia coli endotoxin in cats.
We studied the effects of a selective leukotriene (LT) antagonist (FPL 57231, 2 mg kg-1 min-1) on the acute cardiopulmonary changes observed in feline endotoxin shock. LTC4 and LTD4 (0.1-3.0 micrograms kg-1) given intravenously had little or no activity on pulmonary arterial pressure (PAP), dynamic lung compliance (Cdyn), and airways resistance (Raw). They did, however, produce a systemic hypertension, which was significantly attenuated during the FPL 57231 infusion. E. coli endotoxin (2 mg kg-1) administration resulted in decreases in systemic arterial blood pressure and Cdyn, together with increases in both PAP and Raw. During infusion of FPL 57231, all these endotoxin-induced cardiopulmonary changes were attenuated. Radioimmunoassay of blood samples taken from cats given FPL 57231 showed that levels of 6-keto prosta-glandin F1 alpha and thromboxane B2 were not significantly increased by endotoxin, as would normally be expected in cats administered endotoxin. FPL 57231 was also found to antagonise the pulmonary effects of the thromboxanemimetic U46619 and of prostaglandin F2 alpha. These results indicate that it is unlikely that the leukotrienes are involved as important mediators of the acute phase of endotoxin shock in cats.


Chimeric Antigen Receptor T-cell Therapies in Lymphoma Patients with Central Nervous System Involvement.
CAR T-cell therapy has significantly improved the outcomes of patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). However, most clinical trials excluded patients with central nervous system (CNS) involvement due to uncertain efficacy and safety. On January 1, 2022, we searched PubMed to identify all published literature associated with current commercial CAR T-cell therapies for B-NHL, including tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), and lisocabtagene maraleucel (liso-cel). Studies that involved patients with either primary or secondary CNS lymphoma, and evaluated response rate, adverse events (AEs), or survival were included and summarized. Herein, we summarize the results of 11 studies qualified for our inclusion criteria, reporting 58 lymphoma patients with CNS Involvement with 44 evaluable for clinical response, 25 for immune effector cell-associated neurotoxicity syndrome (ICANS) and 48 for Cytokine release syndrome (CRS). Objective response was achieved in 62% (16/26) of patients, and CR was achieved in 52% (23/44) of patients. Forty-four percent (11/25) developed ICANS, and 35% (17/48) developed severe ICANS (grade≥3). CRS was reported in 63% (15/24) of patients, while severe CRS (grade≥3) was reported in 7% (3/42) of patients. Based on our PubMed literature review, we conclude that CAR T-cell therapy may benefit patients with CNS lymphoma with promising response rates and acceptable AE. However, definite conclusions cannot be drawn until data with a larger sample size is available.


Sparing of folinic acid by thymidine.
Thymidine, which is inactive when added alone to Pediococcus cerevisiae (Leuconostoc citrovorum) 8081, was found to increase its growth in the presence of folinic acid. The addition of thymidine increased both the sensitivity of the folinic acid assay and the total growth yield. The mechanism of the synergistic effect of thymidine is briefly discussed.


Anti-viral Effects of Superpositively Charged Mutant of Green Fluorescent Protein.
Supercharged GFP proteins were known as effective carriers for delivery of macromolecules into eukaryotic cells as well as fluorescent fusion tags for in vitro and in vivo detection. Herein, anti-viral effects of +36 GFP and its anti-tumor effects were studied in vitro and in vivo, respectively. We evaluated anti-HIV, anti-HSV, and anti-HCV effects of +36 GFP in vitro using ELISA, and real time PCR as common techniques for their detection, respectively. Moreover, we assessed the role of +36 GFP for eliciting HPV-related anti-tumor effects in mice due to the lack of HPV replication in vitro. Our data showed that +36 GFP efficiently enter the cells and augment the transfection rate of HPV16E7 antigen, as well. Furthermore, +36 GFP significantly reduced HCV, HIV and HSV replication up to 75%, 49% and 43% in HCV-infected Huh7.5 cells, HIV-infected Hela cells and HSV-infected Vero cells, respectively. On the other hand, mice immunization with +36 GFP complexed with HPV16 E7 antigen (+36GFP + E7) or fused to HPV16 E7 antigen (+36GFP-E7) elicited a higher Th1 cellular immune response with the predominant IgG2a, IgG2b, IFN-γ and Granzyme B levels than those induced by other groups. These regimens protected mice against TC- 1 tumor challenge (~ 67%) compared to E7 protein alone (~ 33%). These data suggested that +36 GFP can act as an anti-viral agent at certain dose due to its high efficiency in cell penetration in vitro and in vivo. Generally, +36 GFP targets viral replication in vitro as well as helps to suppress the growth of HPV-related tumors in vivo.


Structural damage and changes in eicosanoid metabolites in the gastric mucosa of rats and pigs induced by anti-inflammatory drugs of varying ulcerogenicity.
The object of the studies reviewed here has been to correlate the time-course of ultrastructural changes induced by oral administration of a range of non-steroidal anti-inflammatory (NSAI) drugs with effects on eicosanoid metabolism and drug absorption, so as to discriminate what biochemical/cellular and pharmacological factors account for their varying ulcerogenicity. Oral administration of highly ulcerogenic drugs (e.g. aspirin, diclofenac, indomethacin, piroxicam) to rats causes rapid damage to surface and gastric mucous cells, selective parietal cell damage, and extensive disruption of endothelial cells of submucosal microcapillaries (especially with aspirin) with accompanying extravasation of blood cell components. These changes are coincident with depressed levels of PGE2/6-keto-PGF1 alpha (measured by GC/MS or RIA) and uptake of the drugs (measured by scintillation counting or HPLC). Low ulcerogenic NSAI drugs (e.g. azapropazone, benoxaprofen and fenclofenac) causes very little damage to the surface mucosal cells. Azapropazone has been found to be well absorbed, and benoxaprofen and fenclofenac somewhat more slowly, so for the latter two drugs their low rate of absorption might also be a factor in their reduced ulcerogenicity. Aspirin, azapropazone and benoxaprofen have been shown to reduce 5-HETE levels (RIA), although the latter two drugs were more effective than aspirin. Thus, they result in the inhibition of PG production, by cyclo-oxygenase inhibition (with potential adverse effects from excess oxyradical and/or production of HETE's) with inhibition of the lipoxygenase pathway. The time-sequence of changes induced by single oral doses of indomethacin or other NSAI drugs on the ultrastructure and the prostanoid metabolism of the pig gastric mucosa parallelled those seen in the rat. Attempts to determine whether co-administration of NSAI drugs might reduce the inhibition of PG cyclo-oxygenase by more potent inhibitors (e.g. indomethacin) have been explored as a means for reducing the gastric ulcerogenicity of the latter. The results suggest that pharmacokinetic factors may largely account for the reduced ulcerogenicity of these drug mixtures.


Effects of vitamin D3 release from 3D printed calcium phosphate scaffolds on osteoblast and osteoclast cell proliferation for bone tissue engineering.
Vitamin D3 is a hydrophobic micronutrient and is known for inhibiting osteoclastic bone resorption in vivo via suppression of the Receptor Activator of Nuclear factor-Kappa B (RANK ligand) expression in osteoblasts. Although vitamin D is well-known for its promotion in bone health, little is known on its effects directly on bone cells. The objective of this study was to understand the effects of vitamin D3 release from 3D printed calcium phosphate scaffolds towards bone cell proliferation. In this study, cholecalciferol, a common intake form of vitamin D3, was successfully able to release from the scaffold matrix via the use of polyethylene glycol. Results showed a decrease in osteoclast resorption pits and healthier osteoblast cellular morphology compared to the control. Additively manufactured tricalcium phosphate scaffolds with designed porosity were loaded with vitamin D3 and showed controlled release profiles in phosphate buffer and acetate buffer solutions. The release kinetics of vitamin D3 from calcium phosphate scaffolds enabling osteoblast proliferation and inhibiting osteoclastic resorption can enhance healing for low load bearing applications for bone defects or permeate voids left by tumor resection.


Swedish guidelines on the management of community-acquired pneumonia in immunocompetent adults--Swedish Society of Infectious Diseases 2012.
This document presents the 2012 evidence based guidelines of the Swedish Society of Infectious Diseases for the in- hospital management of adult immunocompetent patients with community-acquired pneumonia (CAP). The prognostic score 'CRB-65' is recommended for the initial assessment of all CAP patients, and should be regarded as an aid for decision-making concerning the level of care required, microbiological investigation, and antibiotic treatment. Due to the favourable antibiotic resistance situation in Sweden, an initial narrow-spectrum antibiotic treatment primarily directed at Streptococcus pneumoniae is recommended in most situations. The recommended treatment for patients with severe CAP (CRB-65 score 2) is penicillin G in most situations. In critically ill patients (CRB-65 score 3-4), combination therapy with cefotaxime/macrolide or penicillin G/fluoroquinolone is recommended. A thorough microbiological investigation should be undertaken in all patients, including blood cultures, respiratory tract sampling, and urine antigens, with the addition of extensive sampling for more uncommon respiratory pathogens in the case of severe disease. Recommended measures for the prevention of CAP include vaccination for influenza and pneumococci, as well as smoking cessation.


[Renal extramedullary hematopoiesis. Case report].
Extramedullary hematopoiesis (EMH) is defined as the formation and development of erythrocytic, granulocytic and megakaryocytic cell lines outside the bone marrow; it is a rare occurrence, which is limited to case reports. To describe a case of renal EMH secondary to chronic hypoxia. The patient is a 16 year old teenager who developed chronic hypoxia, central cyanosis, clubbing and lives more than 2,500 m above sea level. Chronic hypoxia is probably secondary to pulmonary hypertension, neither detected nor previously treated. The Consultation was due to a mass in the left upper quadrant for the last three months. An Echocardiogram showed pulmonary hypertension that could not be assessed by hemodynamic parameters. A computed tomography showed bilateral left renal pelvic masses. The hemogram showed polycythemia, so bone marrow aspiration was performed, which rule out malignant pathology. A biopsy of the renal mass reported EMH with three hematopoietic cell lines. This EMH case is a response to chronic hypoxia rather than to a bone marrow lesion as it has usually been described.


Early use of pressure masks to avoid facial contracture during the pregrafting phase.
This article introduces the concept of early application of pressure therapy as a form of splinting in the pregrafting phase. It is based on the principles of (1) the use of pressure therapy to reduce contraction and hypertrophic scar formation and (2) the knowledge that most wound contraction occurs within the initial few weeks of healing. This idea has most application in facial burns, where wound contraction can be disfiguring and functionally disabling, and in situations where unavoidable delay in debridement and grafting may be present. The idea is illustrated with a case report.


Serotonin-immunoreactive neurons in the ventral nerve cord of Remipedia (Crustacea): support for a sister group relationship of Remipedia and Hexapoda?
Remipedia were initially seen as a primitive taxon within Pancrustacea based on characters considered ancestral, such as the homonomously segmented trunk. Meanwhile, several morphological and molecular studies proposed a more derived position of Remipedia within Pancrustacea, including a sister group relationship to Hexapoda. Because of these conflicting hypotheses, fresh data are crucial to contribute new insights into euarthropod phylogeny. The architecture of individually identifiable serotonin-immunoreactive neurons has successfully been used for phylogenetic considerations in Euarthropoda. Here, we identified neurons in three species of Remipedia with an antiserum against serotonin and compared our findings to reconstructed ground patterns in other euarthropod taxa. Additionally, we traced neurite connectivity and neuropil outlines using antisera against acetylated α-tubulin and synapsin. The ventral nerve cord of Remipedia displays a typical rope-ladder-like arrangement of separate metameric ganglia linked by paired longitudinally projecting connectives. The peripheral projections comprise an intersegmental nerve, consisting of two branches that fuse shortly after exiting the connectives, and the segmental anterior and posterior nerve. The distribution and morphology of serotonin-immunoreactive interneurons in the trunk segments is highly conserved within the remipede species we analyzed, which allows for the reconstruction of a ground pattern: two posterior and one anterior pair of serotonin-immunoreactive neurons that possess a single contralateral projection. Additionally, three pairs of immunoreactive neurons are found in the medial part of each hemiganglion. In one species (Cryptocorynetes haptodiscus), the anterior pair of immunoreactive neurons is missing. The anatomy of the remipede ventral nerve cord with its separate metameric ganglia mirrors the external morphology of the animal's trunk. The rope-ladder-like structure and principal architecture of the segmental ganglia in Remipedia corresponds closely to that of other Euarthropoda. A comparison of the serotonin-immunoreactive cell arrangement of Remipedia to reconstructed ground patterns of major euarthropod taxa supports a homology of the anterior and posterior neurons in Pancrustacea. These neurons in Remipedia possess unbranched projections across the midline, pointing towards similarities to the hexapod pattern. Our findings are in line with a growing number of phylogenetic investigations proposing Remipedia to be a rather derived crustacean lineage that perhaps has close affinities to Hexapoda.


Silencing of doublecortin-like (DCL) results in decreased mitochondrial activity and delayed neuroblastoma tumor growth.
Doublecortin-like (DCL) is a microtubule-binding protein crucial for neuroblastoma (NB) cell proliferation. We have investigated whether the anti-proliferative effect of DCL knockdown is linked to reduced mitochondrial activity. We found a delay in tumor development after DCL knockdown in vivo in doxycycline-inducible NB tumor xenografts. To understand the mechanisms underlying this tumor growth retardation we performed a series of in vitro experiments in NB cell lines. DCL colocalizes with mitochondria, interacts with the mitochondrial outer membrane protein OMP25/ SYNJ2BP and DCL knockdown results in decreased expression of genes involved in oxidative phosphorylation. Moreover, DCL knockdown decreases cytochrome c oxidase activity and ATP synthesis. We identified the C-terminal Serine/Proline-rich domain and the second microtubule-binding area as crucial DCL domains for the regulation of cytochrome c oxidase activity and ATP synthesis. Furthermore, DCL knockdown causes a significant reduction in the proliferation rate of NB cells under an energetic challenge induced by low glucose availability. Together with our previous studies, our results corroborate DCL as a key player in NB tumor growth in which DCL controls not only mitotic spindle formation and the stabilization of the microtubule cytoskeleton, but also regulates mitochondrial activity and energy availability, which makes DCL a promising molecular target for NB therapy.


Stable, high-level expression of reporter proteins from improved alphavirus expression vectors to track replication and dissemination during encephalitic and arthritogenic disease.
Engineered alphavirus vectors expressing reporters of infection have been used for a number of years due to their relatively low costs for analysis of virus replication and the capacity to utilize imaging systems for longitudinal measurements of growth within single animals. In general, these vectors have been derived from Old World alphaviruses using a second viral subgenomic promoter to express the transgenes, placed either immediately after the nonstructural proteins or at the 3' end of the viral coding sequences. However, the relevance of these vectors to natural infections is questionable, as they have not been rigorously tested for virulence in vivo in comparison with parental viruses or for the retention of the reporter during replication. Here, we report construction of new expression vectors for two Old World arthritogenic alphaviruses (Sindbis and Chikungunya viruses) and two New World encephalitic alphaviruses (eastern and Venezuelan equine encephalitis viruses) based upon either fusion of the reporter protein in frame within nonstructural protein 3 (nsP3) or insertion of the reporter as a cleavable element between the capsid and PE2 structural proteins. We have compared these with a traditional 3' double subgenomic promoter virus expressing either a large, firefly luciferase (fLuc; 1,650 nucleotides), or small, NanoLuc (nLuc; 513 nucleotides), luminescent reporter protein. Results indicate that the nLuc is substantially more stable than fLuc during repeated rounds of infection regardless of the transgene location. However, the capsid-PE2 insertion and nsP3 fusion viruses exhibit the most authentic mimicking of parental virus infection regardless of expressed protein. IMPORTANCE As more antiviral therapeutics and vaccines are developed, rapid and accurate in vivo modeling of their efficacy will be required. However, current alphavirus vectors expressing reporters of infection have not been extensively tested for accurate mimicking of the infection characteristics of unmodified parental viruses. Additionally, use of in vivo imaging systems detecting light emitted from luciferase reporters can significantly decrease costs associated with efficacy studies by minimizing numbers of animals. Herein we report development and testing of new expression vectors for Sindbis, Chikungunya, and eastern and Venezuelan equine encephalitis viruses and demonstrate that a small (∼500-nucleotide) reporter gene (NanoLuc; Promega) is very stable and causes a disease severity similar to that caused by unmodified parental viruses. In contrast, expression of larger reporters is very rapidly lost with virus replication and can be significantly attenuating. The utility of NanoLuc for in vivo imaging is also demonstrated.


Comparing two seized drug workflows for the analysis of synthetic cannabinoids, cathinones, and opioids.
As the challenges faced by drug chemists persist, due to the presence of emerging drugs, laboratories continue to look for new solutions, ranging from existing methods to implementation of entirely new technology. A common barrier for making workflow changes is a lack of pre-existing data demonstrating the potential impact of these changes. In this study, we compare, qualitatively and quantitatively, an existing workflow for seized drug analysis to an experimental workflow. Four chemists were asked to analyze a total of 50 mock case samples across the two workflows. The existing workflow employed color tests for screening alongside general purpose GC-FID and GC-MS analyses for confirmation. The experimental workflow combined DART-MS screening with class-specific (targeted) GC-MS analysis for confirmation. Comparison of the workflows showed that screening by DART-MS required the same amount of time as color tests but yielded more accurate and specific information. Confirmation using the existing workflow required more than twice the amount of instrument time and data interpretation time while also presenting other analytical challenges that prevented compound confirmation in select samples. Targeted GC-MS methods simplified data interpretation, reduced consumption of reference materials, and addressed almost all limitations of general-purpose methods. While the experimental workflow requires modifications and answering of additional research questions, this study shows how rethinking analytical workflows for seized drug analysis could reduce turnaround times, backlogs, and standards consumption. It also demonstrates the potential impact of being able to investigate workflow changes prior to implementation.


Life cycle assessment of biodiesel production in China.
This study aims to evaluate energy, economic, and environmental performances of seven categories of biodiesel feedstocks by using the mixed-unit input-output life cycle assessment method. Various feedstocks have different environmental performances, indicating potential environmental problem-shift. Jatropha seed, castor seed, waste cooking oil, and waste extraction oil are preferred feedstocks for biodiesel production in the short term. Positive net energy yields and positive net economic benefits of biodiesel from these four feedstocks are 2.3-52.0% of their life cycle energy demands and 74.1-448.4% of their economic costs, respectively. Algae are preferred in the long term mainly due to their less arable land demands. Special attention should be paid to potential environmental problems accompanying feedstock choice: freshwater use, ecotoxicity potentials, photochemical oxidation potential, acidification potential and eutrophication potential. Moreover, key processes are identified by sensitivity analysis to direct future technology improvements. Finally, supporting measures are proposed to optimize China's biodiesel development.


Interaction of endothelin-1 and nitric oxide pathways in human tubular epithelial cells under the influence of cyclosporine-A.
The exact mechanism of cyclosporine (CsA) nephrotoxicity has not been clarified. In this study, we investigated the effect of pharmacological doses of CsA on the production of nitric oxide synthases (NOSs) and endothelin (ET) receptors (ETR-A, ETR-B), in human tubular cells [human kidney (HK)-2], to identify any implication of these pathways in CsA nephrotoxicity. Human tubular epithelial cells (HK-2) were cultured in the presence of CsA at various concentrations (0-1000 ng/mL). Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine mRNA synthesis of NOSs (eNOS, iNOS) and ET receptors (ETR-A, ETR-B) and western blot analysis for the subsequent proteins. A dose-dependent induction of synthesis of NO synthases eNOS and iNOS and ET receptors ETR-A and ETR-B was observed, even at therapeutic doses of CsA. An interaction between NO and ET-1 systems under the influence of CsA was also observed. Blockage of NO production was followed by down-regulation of ETR-B whereas blockade of ET pathway with ET receptor antagonists was followed by down-regulation of eNOS expression. CsA induces NOSs as well as ET receptor mRNA and protein synthesis in tubular epithelial cells. The up-regulation of NO and ET-1 pathways is probably implicated in the nephrotoxic action of CsA, whereas an interplay between ETR-B and eNOS seems to be involved.


Hybridoma cultivation in defined serum-free media: growth-supporting substances. I. Transferrin.
Effect of transferrin and effect of transferrin omission on growth of hybridomas in serum-free medium were studied. Transferrin at concentration 0.5 microgram/ml and higher concentrations stimulated growth of hybridoma cells. The optimum growth-supporting concentration of transferrin was 5 micrograms/ml. Omission of transferrin led to death of hybridoma T3-03 cells within 3-4 days. Omission of transferrin for a period of only 24 h damaged cells so severely, that they were unable to recover fully.


Wastewater management approach in an industrial park.
Many industrial parks adopt a two-tier wastewater management framework whereby tenants and the park are required to build satellite and centralized wastewater treatment facilities, respectively. Due to the diversity of industrial wastewaters, the treatment process scheme in the public centralized wastewater treatment plant (WWTP) may not suit the characteristics of all effluents discharged from the tenants. In consideration of varying wastewater biodegradability, the treatment scheme in a centralized WWTP is advised to install two series of treatment processes. In detail, various effluents from the tenants shall be commingled according to their levels of biodegradability. For the non-biodegradable streams, advanced oxidation processes shall be applied in addition to biological treatments. To facilitate the grouping of effluents, each effluent will be evaluated for its biodegradability. An analytical protocol derived from OECD standard (TG302B) was developed and found effective for biodegradability assessment. A case study is described in this paper to showcase the methodology.


Structure and function of the Groucho gene family and encoded transcriptional corepressor proteins from human, mouse, rat, Xenopus, Drosophila and nematode.
A gene family of the Groucho, TLE, ESG and AES proteins has been characterized from Drosophila, nematode, Xenopus, mouse, rat and human, and their structural relationships have been analyzed. The genomic organization of nematode ESG, human and mouse AES genes has been determined, and the expression of ESG and AES genes from Xenopus and human has been analyzed. The Groucho, TLE and ESG proteins all share a similar structure, consisting of a conserved amino-terminal domain, a variable middle region, and highly conserved carboxyl-terminal WD-40 repeats. The Drosophila Groucho transcriptional corepressor protein has been shown to interact with the DNA-binding bHLH domain of Enhancer of split, Hairy and Deadpan proteins, which proteins are involved in neurogenesis, segmentation and sex-determination, respectively. Human TLE1 protein has been demonstrated to interact with mammalian AML1 protein, which regulates hematopoiesis and osteoblast differentiation. The AES proteins from human, mouse, rat and Xenopus exhibit strong similarity to the amino-terminal domain of Groucho proteins; however, the biological function remains to be elucidated.


Exploring the use of soft X-ray microscopy for imaging subcellular structures of the inner ear.
The soft X-ray microscope at the Lawrence Berkeley National Laboratory was developed for visualization of biological tissue. Soft X-ray microscopy provides high-resolution visualization of hydrated, non-embedded and non-sectioned cells and is thus potentially an alternative to transmission electron microscopy. Here we show for the first time soft X-ray micrographs of structures isolated from the guinea-pig inner ear. Sensory outer hair cells and supporting pillar cells are readily visualized. In the hair cells, individual stereocilia can easily be identified within the apical hair bundle. The underlying cuticular plate is, however, too densely composed or too thick to be clearly visualized, and thus appears very dark. The cytoplasmic structures protruding from the cuticular plates as well as the fibrillar material surrounding and projecting from the cell nuclei can be seen. In the pillar cells the images reveal individual microtubule bundles. Soft X-ray images of the acellular tectorial membrane and thin two-layered Reissner's membrane display a level of resolution comparable to low-power electron microscopy.


Targeting cell cycle kinases and kinesins in anticancer drug development.
The cell cycle is regulated by kinases such as the cyclin-dependent kinases (CDKs) and non-CDKs, which include Aurora and polo-like kinases, as well as checkpoint proteins. Mitotic kinesins are involved in the establishment of the mitotic spindle formation and function, and also play a role in cell cycle control. The disruption of the cell cycle is a hallmark of malignancy. Genetic or epigenetic events result in the upregulation of these kinases and mitotic kinesins in a myriad of tumour types, suggesting that their inhibition could result in preferential targeting of malignant cells. Such findings make the development of these inhibitors a rational and attractive new area for cancer therapeutics. Although challenges of potency and non-specificity have hampered their progress through the clinic, several novel compounds are presently in various phases of clinical trial evaluation.


HIV/STD risk reduction interventions for African American and Latino adolescent girls at an adolescent medicine clinic: a randomized controlled trial.
Adolescent girls in the United States and around the world are at a heightened risk for sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV). To determine the efficacy of a skill-based HIV/STD risk-reduction intervention in reducing self-reported unprotected sexual intercourse among African American and Latino adolescent girls. Randomized controlled trial with 3-, 6-, and 12-month follow-ups. Sexually experienced African American and Latino adolescent girls recruited from the adolescent medicine clinic of a children's hospital serving a low-income inner-city community (N = 682, mean age, 15.5 years); 88.6% were retained at the 12-month follow-up. Three 250-minute interventions based on cognitive-behavioral theories and elicitation research: an information-based HIV/STD intervention provided information necessary to practice safer sex; a skill-based HIV/STD intervention provided information and taught skills necessary to practice safer sex; or a health-promotion control intervention concerned with health issues unrelated to sexual behavior. Primary outcome measure was self-reported frequency of unprotected sexual intercourse; secondary outcomes included the frequency of sexual intercourse while intoxicated, the number of sexual partners, biologically confirmed STDs, and theoretical mediator variables, including the intention to use condoms, beliefs about using condoms, and condom-use knowledge. No differences between the information intervention and the health control intervention were statistically significant. Skills-intervention participants (mean [SE], 2.27 [0.81]) reported less unprotected sexual intercourse at the 12-month follow-up than did information-intervention participants (mean [SE], 4.04 [0.80]; P = .03), or health control-intervention participants (mean [SE], 5.05 [0.81]; P = .002). At the 12-month follow-up, skills-intervention participants (mean [SE], 0.91 [0.05]) reported fewer sexual partners (P = .04) compared with health control-intervention participants (mean [SE], 1.04 [0.05]) and were less likely to test positive for STD (mean [SE], 10.5% [2.9%]) than were health control-intervention participants (mean [SE], 18.2% [2.8%]; P = .05). No differences in the frequency of unprotected sexual intercourse, the number of partners, or the rate of STD were observed at the 3- or 6-month follow-up between skill-intervention participants and information-intervention or health control-intervention participants. Skill-based HIV/STD interventions can reduce sexual risk behaviors and STD rate among African American and Latino adolescent girls in clinic settings.


Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells.
In a series of human corticotroph adenomas, we recently found predominant mRNA expression of somatostatin (SS) receptor subtype 5 (sst5). After 72 h, the multiligand SS analog SOM230, which has a very high sst5 binding affinity, but not Octreotide (OCT), significantly inhibited basal ACTH release. To further explore the role of sst5 in the regulation of ACTH release, we conducted additional studies with mouse AtT-20 cells. SOM230 showed a 7-fold higher ligand binding affinity and a 19-fold higher potency in stimulating guanosine 5'-O-(3-thiotriphosphate) binding in AtT-20 cell membranes compared with OCT. SOM230 potently suppressed CRH-induced ACTH release, which was not affected by 48-h dexamethasone (DEX) pretreatment. However, DEX attenuated the inhibitory effects of OCT on ACTH release, whereas it increased the inhibitory potency of BIM-23268, an sst5-specific analog, on ACTH release. Quantitative PCR analysis showed that DEX lowered sst(2A+2B) mRNA expression significantly after 24 and 48 h, whereas sst5 mRNA levels were not significantly affected by DEX treatment. Moreover, Scatchard analyses showed that DEX suppressed maximum binding capacity (B(max)) by 72% when 125I-Tyr3-labeled OCT was used as radioligand, whereas B(max) declined only by 17% when AtT-20 cells were treated with [125I-Tyr11]SS-14. These data suggest that the sst5 protein, compared with sst2, is more resistant to glucocorticoids. Finally, after SS analog preincubation, compared with OCT both SOM230 and BIM-23268 showed a significantly higher inhibitory effect on CRH-induced ACTH release. In conclusion, our data support the concept that the sst5 receptor might be a target for new therapeutic agents to treat Cushing's disease.


The role of Mg2+ and Mn2+ in the enzyme-catalysed activation of nitrogenase Fe protein from Rhodospirillum rubrum.
The activation of the Fe protein of nitrogenase (Rr2) from glutamate-grown Rhodospirillum rubrum by activating enzyme (AE) was investigated. AE is confirmed to have Mr about 20 000 and is shown to operate catalytically. There is a role in activation for metal-ion-ATP, which can be met by either MnATP or MgATP. There is also a site of action for free metal ions. This site prefers Mn2+ (apparent Kd approx. 20 microM) over Mg2+ (apparent Kd approx. 20 mM) by a factor of 1000-fold. Non-activated Rr2 does not contain this binding site. MnATP is an inhibitor of C2H2 reduction, and excess Mg2+ inhibits both AE activity and C2H2 reduction, when each is studied independently under otherwise optimal conditions. The activity of AE is increased in normal reaction mixtures (in which AE activity and nitrogenase activity occur simultaneously) by Mg2+ concentrations in excess of ATP concentrations; this occurs because the excess Mg2+ prevents ATP from chelating the free Mn2+ necessary for optimal AE activity.


Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis.
Biological aging measures have been proposed as proxies for extension of healthy life span in trials of geroprotective therapies that aim to slow aging. Several methods to measure biological aging show promise but it is not known if these methods are sensitive to changes caused by geroprotective therapy. We conducted analysis of two proposed methods to quantify biological aging using data from a recently concluded trial of an established geroprotector, caloric restriction. We obtained data from the National Institute on Aging CALERIE randomized trial through its public-access biobank (https://calerie.duke.edu/). The CALERIE trial randomized N = 220 nonobese adults to 25% caloric restriction (n = 145; 11.7% caloric restriction was achieved, on average) or to maintain current diet (n = 75) for 2 years. We analyzed biomarker data collected at baseline, 12-, and 24-month follow-up assessments. We applied published biomarker algorithms to these data to calculate two biological age measures, Klemera-Doubal Method Biological Age and homeostatic dysregulation. Intent-to-treat analysis using mixed-effects growth models of within-person change over time tested if caloric restriction slowed increase in measures of biological aging across follow-up. Analyses of both measures indicated caloric restriction slowed biological aging. Weight loss did not account for the observed effects. Results suggest future directions for testing of geroprotective therapies in humans.


Low-dose CT protocol for orthodontic diagnosis.
This was to correlate the dosimetric evaluation with high diagnostic accuracy by suggesting a protocol that significantly reduces the dose administered by a Dentascan exam without affecting diagnostic accuracy. 17 patients were selected consecutively (7 males and 10 females) of a mean age of 11.2 (8-14 years) who sought orthodontic treatment. They needed CT control before and after treatment with RME to evaluate impacted canines. The study was performed using a multidetector 16-rows CT with two protocols that provided 2 different KV acquisition parameters: 80 KV or 120 KV. Radiation dose was evaluated in two ways: CTDI and DLP. Image quality was rated and the results were compared to identify significant differences in terms of image quality, radiation exposure and presence of artefacts. The 80 KV scanning has a significantly lower effective radiation dose compared to the 120 KV scanning (p <0.05). The images of all patients were used for comparing the protocols in terms of image quality. The mean scores for the 80 KV scanning images were 4.18 +/-0.81 and 4.41 +/-0.80 for dose obtained by 120 KV scanning. The median image quality was 4 (good) for both protocols. The 80 KV protocol allowed, as well as the 120 KV, a careful analysis by the orthodontist and the dental surgeon that together, based on this images, can choose the best line of treatment between several available options. 80 KV protocols compared with 120 KV protocols resulted in reduced total radiation dose without relevant loss of diagnostic image information and quality. The images were good enough to obtain information about the exact position of impacted teeth and to plan the best line of surgical treatment and mechanotherapy strategy.


Body mass and V'O2 at rest affect gross efficiency during moderate-intensity cycling in untrained young healthy men: correlations with V'O2MAX.
Seventeen young healthy physically active males (age 23 ±3 years; body mass (BM) 72.5 ±7.9 kg; height 178 ±4 cm, (mean ±SD)), not specifically trained in cycling, participated in this study. The subjects performed two cycling incremental tests at the pedalling rate of 60 rev x min-1. The first test, with the power output (PO) increases of 30 W every 3 min, was to determine the maximal oxygen uptake (V'O2max) and the power output (PO) at V'O2max, while the second test (series of 6 minutes bouts of increasing intensity) was to determine energy expenditure (EE (V'O2)), gross efficiency (GE (V'O2/PO)) and delta efficiency (DE(ΔV'O2/DPO)) during sub-lactate threshold (LT) PO. V'O2max was 3.79 ±0.40 L x min-1 and the PO at V'O2max was 288 ±27 W. In order to calculate GE and DE the V'O2 was expressed in W, by standard calculations. GE measured at 30 W, 60 W, 90 W and 120 W was 11.6 ±1.4%, 17.0 ±1.4%, 19.6 ±1.2% and 21.4 ±1.1%, respectively. DE was 29.8 ±1.9%. The subjects' BM (range 59-87 kg) was positively correlated with V'O2 at rest (p<0.01) and with the intercept of the linear V'O2 vs. PO relationship (p<0.01), whereas no correlation was found between BM and the slope of V'O2 vs. PO. No correlation was found between BM and DE, whereas GE was negatively correlated with BM (p<0.01). GE was also negatively correlated with V'O2max and the PO at V'O2max (p<0.01). We conclude that: V'O2 at rest affects GE during moderate-intensity cycling and GE negatively corelates with V'O2max and the PO at V'O2max in young healthy men.


Biochemical studies of acetylcholine esterase inhibitor present in Eugenia caryophyllus.
Water, saline and ethanol extracts of Eugenia caryophyllus inhibited brain acetylcholinesterase (AchE) activity. Inhibitory action of the saline extract was greater than that of other extracts. The most active fraction of the saline extract obtained by chromatography through Sephadex G25 and DEAE cellulose columns and elution with tris and phosphate buffers (pH. 7.1) exhibited reactions characteristic of phenols, amino compounds and uronic acid. It is, therefore, suggested that the active inhibitor is a complex glycoside containing phenol and uronic acid part structure.


Differential expression of TRPM7 in rat hepatoma and embryonic and adult hepatocytes.
TRPM7 channels are implicated in cellular survival, proliferation, and differentiation. However, a profile of TRPM7 activity in a specific cell type has not been determined from embryonic to terminally differentiated state. Here, we characterized TRPM7 expression in a spectrum of rat liver cells at different developmental stages. Using the whole-cell patch clamp technique, TRPM7-like Na(+) currents were identified in RLC-18 cells, a differentiated, proliferating hepatocellular line derived from day 17 embryonic rat liver. Currents were outwardly rectifying, enhanced in divalent-free solutions, and inhibited by intracellular Mg(2+). Reverse transcription - polymerase chain reaction (RT-PCR) revealed that RLC-18 cells express both TRPM6 and TRPM7. However, mean currents were reduced almost 80% by 1 mmol/L 2-aminoethoxyphenylborate (2-APB) and were abolished in RLC-18 cells heterologously expressing a dominant negative TRPM7 construct, suggesting that TRPM7 is the major current carrier in these cells. Functional comparison showed that relative to terminally differentiated adult rat hepatocytes, currents were 1.8 and 3.9 times higher in, respectively, RLC-18 and WIF-B cells, a rat hepatoma - human fibroblast cross. Our results demonstrate that plasma membrane TRPM7 channels are more highly expressed in proliferating cells as compared with terminally differentiated and nondividing rat hepatocytes and suggest that downregulation of this channel is associated with hepatocellular differentiation.


Oestrogen receptors in human breast cancer: review of histopathological correlations and critique of histochemical methods.
Correlations between the oestrogen receptor (ER) content and histology of human breast cancer are reviewed. Although conventional receptor assays of tissue homogenates may give misleading results because of tumour heterogeneity, certain trends are apparent: lobular carcinomas are rather more commonly ER positive than are ductal carcinomas; cellularity, differentiation, elastosis, and paucity of stromal lymphocytes are positively correlated with ER content in ductal carcinomas. Attempts to detect and localize steroid hormone binding sites in breast cancer cells or sections by histochemical or immunohistochemical methods do not satisfy the criteria for demonstrating classical high affinity cytosolic receptors. Nevertheless, the clinical relevance of demonstrating binding sites of lower affinity may be worthy of further investigation. Breast cancer is an ideal model for exploring correlations between structure and function in tumours.


[The possibility of the serum concentration of osteocalcin determination in lung cancer patients with suspected bone metastases].
The aim of this study was to compare serum levels of biochemical markers of bone metabolism - osteocalcin (OC) in correlation with bone metastases found during whole-body bone scintigraphy in patients with lung cancer. The serum levels of OC as a bone formation marker were determined in 60 patients (46 male, 14 female, mean age 66.65, range 50-84 years) with lung cancer (51 non-small-cell lung cancers - NSCLC and nine small-cell lung cancers - SCLC) and correlated with the presence of bone metastases detected by whole-body bone scintigraphy (hybrid system SPECT/CT: BrightView XCT, Philips Healthcare). Whole-body bone scintigraphy results were compared with OC for each patient with lung cancer and for person from control group of 10 persons (two males, eight females, mean age 52.3, range 34-67 years) with-out malignant disease. By whole-body bone scintigraphy, bone metastases were found in 15 cases (25%), probably in 11 cases (18.33%) and 34 patients (56.67%) were without bone metastases out of 60 patients with lung cancer. The serum levels of OC were above reference range in five cases (8.33%) only with NSCLC and below reference range in 12 cases (20%) - in 10 cases in patients with NSCLC and in two cases in patients with SCLC. In control group of 10 persons, serum level of OC was below reference range only in one case. The serum concentrations of osteocalcin were not correlated with findings performed bywhole-body bone scintigraphy in patients with lung cancer. Osteocalcin serum levels determination probably does not have diagnostic importance in lung cancer patients with suspected bone metastases.


Efficacy of skin-directed therapy for cutaneous metastases from advanced cancer: a meta-analysis.
To perform the first meta-analysis of the efficacy of skin-directed therapies for cutaneous metastases. MEDLINE, EMBASE, The Cochrane Library, and ClinicalTrials.gov databases were searched for reports of prospective clinical studies published between 1960 and 2013 that assessed the response of skin-directed therapy for cutaneous metastases (47 of 2,955 unique studies were selected). Primary end points of the study were complete and objective response rates. Secondary analyses were preplanned and included subgroup analyses by skin-directed therapy, histology, and recurrence rates. Meta-analyses were performed with random-effect modeling, and extent of heterogeneity between studies was determined with the Cochran Q and I(2) tests. After applying exclusion criteria, 47 prospective studies of 4,313 cutaneous metastases were assessed. Five skin-directed therapies were identified: electrochemotherapy, photodynamic therapy, radiotherapy, intralesional therapy, and topical therapy. Among all cutaneous metastases, complete response rate was 35.5% (95% CI, 27.6% to 44.3%) and objective response rate was 60.2% (95% CI, 50.6% to 69.0%). Overall recurrence rate was estimated to be 9.2% (95% CI, 3.7% to 21.2%). Melanoma and breast carcinoma comprised 96.8% of all cutaneous metastases studied and had similar objective response rates (54.5% [95% CI, 48.3% to 60.7%] and 54.0% [95% CI, 48.3% to 59.7%], respectively). Grade ≥ 3 toxicity was reported in less than 6% of patients. Response to skin-directed therapy for cutaneous metastases is high but heterogeneous across treatment modalities, with low rates of recurrence post-treatment. Treatment was generally well tolerated and conferred improvements in quality of life. Standardization of response criteria for cutaneous metastases and treatment algorithms to optimally use the available skin-directed therapies are needed.


Removal of ciprofloxacin from aqueous solution by electro-activated persulfate oxidation using aluminum electrodes.
The aim of this study was to determine the removal of ciprofloxacin (CIP) by the electro-persulfate (EC-PS) process using aluminum (Al) electrodes. The effects of variables including pH, contact time, PS concentration, initial CIP concentration and current density on the removal efficiency of CIP were studied. In order to determine the mechanisms of the EC-PS process, the radical scavenger tests, as well as energy dispersive spectroscopy (EDS) and Fourier transform infrared spectroscopy (FT-IR) were performed on the sludge. The results showed that the PS process alone had no effect on the CIP removal, and the EC process alone could remove 25% of CIP after 160 min. However, the EC-PS process under the optimum conditions: pH of 7, time of 40 min, current density of 2.75 mA/cm2, CIP concentration of 20 mg/L, and PS concentration of 0.84 mM removed 90% of CIP. The effect of the EC-PS process on the actual hospital wastewater was 81% in optimal conditions. The kinetic study also showed that the second-order kinetic model was the most consistent. The oxidation process during the initial contact was dominant in the EC-PS process and, over time, the EC process was dominant for CIP removal.


Acquired aortic regurgitation following occlusion of the persistent arterial duct: an echocardiographic assessment.
To document the development of aortic regurgitation following occlusion of a patent arterial duct. Case series involving nine children referred for surgical ligation of an isolated patent arterial duct. Academic referral centre. A preoperative transthoracic and transoesophageal echocardiogram was performed in theatre to look for aortic regurgitation. Thereafter, aortic flow was monitored throughout the operation by colour flow mapping with the transoesophageal probe in situ. Onset of aortic regurgitation was documented. An immediate postoperative transthoracic echocardiogram was performed on all patients and then daily until discharge on day 5. A follow up clinical and echocardiographic assessment was performed six weeks postoperatively. With ligation of the patient arterial duct, transoesophageal echocardiography showed immediate regurgitation in seven of the nine patients, seen as a small central jet on colour flow mapping. Six of the seven patients continued to have aortic regurgitation on transthoracic echocardiography before leaving theatre. In none was aortic regurgitation audible clinically. At discharge, five patients still had evidence of aortic regurgitation; of four seen at follow up six weeks later, only one had residual regurgitation. Ligation of the patient arterial duct results in the acute termination of the "run off" in a volume overloaded situation. This, together with a rise in the peripheral vascular resistance and the persistence of increased proximal vascular capacitance, is considered to be the underlying aetiology of the acquired aortic regurgitation.


Ecological adaptation determines functional mammalian olfactory subgenomes.
The ability to smell is governed by the largest gene family in mammalian genomes, the olfactory receptor (OR) genes. Although these genes are well annotated in the finished human and mouse genomes, we still do not understand which receptors bind specific odorants or how they fully function. Previous comparative studies have been taxonomically limited and mostly focused on the percentage of OR pseudogenes within species. No study has investigated the adaptive changes of functional OR gene families across phylogenetically and ecologically diverse mammals. To determine the extent to which OR gene repertoires have been influenced by habitat, sensory specialization, and other ecological traits, to better understand the functional importance of specific OR gene families and thus the odorants they bind, we compared the functional OR gene repertoires from 50 mammalian genomes. We amplified more than 2000 OR genes in aquatic, semi-aquatic, and flying mammals and coupled these data with 48,000 OR genes from mostly terrestrial mammals, extracted from genomic projects. Phylogenomic, Bayesian assignment, and principle component analyses partitioned species by ecotype (aquatic, semi-aquatic, terrestrial, flying) rather than phylogenetic relatedness, and identified OR families important for each habitat. Functional OR gene repertoires were reduced independently in the multiple origins of aquatic mammals and were significantly divergent in bats. We reject recent neutralist views of olfactory subgenome evolution and correlate specific OR gene families with physiological requirements, a preliminary step toward unraveling the relationship between specific odors and respective OR gene families.


[Clinical morphology of hypersensitivity pneumonitis].
The article presents a viewpoint on morphogenesis types of dust pulmonary diseases and details clinical morphology of hypersensitivity pneumonitis, based on lung biopsy studies in industrial workers.


A comparison of concentrations of polycyclic aromatic compounds detected in dust samples from various regions of the world.
Settled house dust can be a source of human exposure to toxic polycyclic aromatic hydrocarbons (PAHs) through non-dietary ingestion and dermal contact. Information regarding the concentrations of various contaminants in house dust would be useful in estimating the risk associated with exposure to these compounds. This study reports on the surface loading, variability and distribution of PAHs in settled house dust collected from homes in three locations: Sumgayit, Azerbaijan; Shanxi Province, China; and southern Texas, United States. The highest PAH floor surface loadings were observed in China, followed by Azerbaijan and Texas. Median concentrations of high molecular weight (four ring and larger) PAHs ranged from a low of 0.11 microg/m(2) in Texas, to 2.9 microg/m(2) in Azerbaijan and 162 microg/m(2) in China. These trends in total surface loading and relative carcinogenicity indicate that the risk of health effects from exposure to PAHs in house dust is highest in the Chinese population and lowest in the Texas population. As anticipated, variability among dust samples from different houses within the same region was high, with coefficients of variation greater than 100%. Alkylated PAHs comprised 30-50% of the total mass of PAHs. Based on a comparison of the composition of specific components, PAHs in China and Azerbaijan were determined to be derived mainly from combustion sources rather than from unburned fossil fuels such as petroleum. These results, coupled with ongoing investigation of appropriate PAH exposure biomarkers in humans, will guide future efforts to identify ways to reduce exposures in the study areas.


Exploring in-session focus on the patient-therapist relationship: patient characteristics, process and outcome.
This study explored the amount of in-session focus on the patient-therapist relationship during early treatment with patient pre-treatment interpersonal style, personality pathology, patient ratings of session process and outcome. The sample consisted of 76 outpatients engaged in short-term psychodynamic psychotherapy. Results showed that higher levels of pre-treatment personality pathology and interpersonal problems were positively related to a greater focus on the patient-therapist relationship early in treatment. This was especially true for patients with a cold/distant interpersonal style and low self-esteem. Moreover, these two patient pre-treatment characteristics demonstrated a significant change over the course of therapy. These post-treatment changes also demonstrated a significant relationship with greater early treatment focus on the patient-therapist relationship. In addition, we found an interaction effect between quality of object relations (i.e., higher levels of object relations) and greater early treatment focus on the patient-therapist relationship with subsequent changes in patient cold/distant interpersonal problems. Greater in-session focus on the therapeutic relationship was not significantly related to patient ratings of session process. Implications for clinical practice and future research are discussed.


Mid- and Long-Term Outcome Comparisons of Everolimus-Eluting Bioresorbable Scaffolds Versus Everolimus-Eluting Metallic Stents: A Systematic Review and Meta-analysis.
Percutaneous coronary interventions to implant bioresorbable vascular scaffolds (BVSs) were designed to reduce the late thrombotic events that occur with metallic stents. To estimate the incidence of scaffold thrombosis after BVS implantation and compare everolimus-eluting BVSs with everolimus-eluting metallic stents (EESs) in terms of safety and efficacy at mid- and long-term follow-up in adults who had a percutaneous coronary intervention. PubMed, EMBASE, the Cochrane Library, conference proceedings, and relevant Web sites from inception until 20 May 2017, without language restriction. 7 randomized trials and 38 observational studies (each with a minimum of 6 months and 100 patient-years of follow-up) in adults with coronary artery disease who had a BVS or an EES and reported scaffold or stent thrombosis (main outcome) or other secondary outcomes (such as death, myocardial infarction, or revascularization). 2 reviewers independently extracted study data, rated study quality, and assessed strength of evidence. The pooled incidence of definite or probable scaffold thrombosis after BVS implantation was 1.8% (95% CI, 1.5% to 2.2%) at a median follow-up of 1 year (41 studies, 21 884 patients) and 0.8% (CI, 0.5% to 1.3%) beyond 1 year (14 studies, 4688 patients). Seven trials involving 5578 patients that directly compared BVSs with EESs showed an increased risk for definite or probable scaffold thrombosis (odds ratio [OR], 3.40 [CI, 2.01 to 5.76]) with BVSs at a median follow-up of 25 months. Increased risks were present at early (prominently subacute), late, and very late stages, and odds beyond 1 year were almost double those seen within 1 year. Bioresorbably vascular scaffolds increased risks for myocardial infarction (OR, 1.63 [CI, 1.26 to 2.10]), target lesion revascularization (OR, 1.31 [CI, 1.03 to 1.67]), and target lesion failure (OR, 1.37 [CI, 1.12 to 1.66]); the odds for these 3 end points also increased over time. The incidences of all-cause, cardiac, and noncardiac death and of target vessel and any revascularization did not differ. Quality of observational studies was unclear, and some data were unpublished. Compared with EESs, BVSs increased the risks for scaffold thrombosis and other thrombotic events at mid- and long-term follow-up, and risks increased over time. National Natural Science Foundation of China.


A paper based microfluidic device for easy detection of uric acid using positively charged gold nanoparticles.
A paper based microfluidic device is fabricated that can rapidly detect very low concentrations of uric acid (UA) using 3,5,3',5'-tetramethyl benzidine (TMB), H2O2 and positively charged gold nanoparticles ((+)AuNPs). In the presence of (+)AuNPs, H2O2 reacts with TMB to produce a bluish-green colour which becomes colourless on reaction with UA. This colorimetric method can detect as low as 8.1 ppm of UA within <20 minutes on white filter paper. This technique provides an alternative way for UA detection.


Decreased fasting and oral glucose stimulated C-peptide in nondiabetic subjects with sequence variants in the sulfonylurea receptor 1 gene.
The high-affinity sulfonylurea receptor 1 (SUR1) plays an important role in regulating insulin secretion. In the Québec Family Study, we genotyped 731 individuals (685 nondiabetic [ND] subjects) for the SUR1 gene IVS15-3c-->t and exon 18 Thr759(ACC-->ACT) polymorphisms using polymerase chain reaction-restriction fragment-length polymorphism analysis. Phenotypes measured were fasting plasma glucose (GLU), fasting plasma insulin (INS), and fasting C-peptide (CPEP), as well as oral glucose tolerance test (OGTT) responses; they were adjusted for age, sex, waist circumference, and the sum of six skinfold thicknesses. In ND subjects, exon 18 Thr759(ACC-->ACT) T allele carriers (T+) had lower CPEP (P = 0.022, -12.8%) and acute C-peptide responses (area above basal in first 30 min [CP30]) (P = 0.051, -12.4%) than noncarriers (T-). Also, in those with the cT/tC haplotype (from both IVS15-3c-->t and exon 18 Thr759[ACC-->ACT] polymorphisms), CPEP (P = 0.005, -21.2%), CP30 (P = 0.034, -19.2%), and total C-peptide responses (P = 0.016, -20.2%) were lower than that in cT- subjects. In overweight individuals (BMI >25 kg/m2), differences between carriers and noncarriers of the T or cT alleles were greater for GLU (P = 0.023-0.034), CPEP (P = 0.021-0.015), acute OGTT insulin response (P = 0.014-0.019), and CP30 (P = 0.034-0.019). These results suggest that the T and cT allele variants are associated with lower insulin secretion parameters, particularly in female and overweight subjects, adding evidence to the role of SUR1 sequence variants in decreased insulin secretion.


The journey to becoming a research nurse.
Clinical trials nurses are in a unique position to actively engage in many aspects of cancer research and scientific inquiry. Opportunities range from research nurse to data manager to and protocol treatment nurse. Each role encompasses responsibilities and tasks critical to ensuring the protection of human subjects and credible clinical trials data. Federal regulations serve as guides to direct practice and for the purpose of applying ethical principles. A case study describing an oncology nurse's transition to the research role is presented.


At the interface of community and healthcare systems: a longitudinal cohort study on evolving health and the impact of primary healthcare from the patient's perspective.
Massive efforts in Canada have been made to renew primary healthcare. However, although early evaluations of initiatives and research on certain aspects of the reform are promising, none have examined the link between patient assessments of care and health outcomes or the impacts at a population level. The goal of this project is to examine the effect of patient-centred and effective primary healthcare on the evolution of chronic illness burden and health functioning in a population, and in particularly vulnerable groups: the multi-morbid and the poor. A randomly selected cohort of 2000 adults aged 25 to 75 years will be recruited within the geographic boundaries of four local healthcare networks in Quebec. At recruitment, cohort members will report on socio-demographic information, functional health and healthcare use. Two weeks, 12 months and 24 months after recruitment, cohort participants will complete a self-administered questionnaire on current health and health behaviours in order to evaluate primary healthcare received in the previous year.The dependent variables are calculated as change over time of functional health status, chronic illness burden, and health behaviours. Dimensions of patient-centred care and clinical processes are measured using sub-scales of validated instruments. We will use Poisson regression modelling to estimate the incidence rate of chronic illness burden scores and structural equation modelling to explore relationships between variables and to examine the impact of dimensions of patient-centred care and effective primary healthcare. Results will provide valuable information for primary healthcare clinicians on the course of chronic illness over time and the impact on health outcomes of accessible, patient-centred and effective care. A demonstration of impact will contribute to the promotion of continuous quality improvement activities at a clinical level. While considerable advances have been made in the management of specific chronic illnesses, this will make a unique contribution to effective care for persons with multiple morbidities. Furthermore, the cohort and data architecture will serve as a research platform for future projects.


Super-hydration and reduction of manganese oxide minerals at shallow terrestrial depths.
Manganese oxides are ubiquitous marine minerals which are redox sensitive. As major components of manganese nodules found on the ocean floor, birnessite and buserite have been known to be two distinct water-containing minerals with manganese octahedral interlayer separations of ~7 Å and ~10 Å, respectively. We show here that buserite is a super-hydrated birnessite formed near 5 km depth conditions. As one of the most hydrous minerals containing ca. 34.5 wt. % water, super-hydrated birnessite, i.e., buserite, remains stable up to ca. 70 km depth conditions, where it transforms into manganite by releasing ca. 24.3 wt. % water. Subsequent transformations to hausmannite and pyrochroite occur near 100 km and 120 km depths, respectively, concomitant with a progressive reduction of Mn4+ to Mn2+. Our work forwards an abiotic geochemical cycle of manganese minerals in subduction and/or other aqueous terrestrial environments, with implications for water storage and cycling, and the redox capacity of the region.


Exposure to organophosphorus compounds: best practice in managing timely, effective emergency responses.
Increasing indications, reports and studies demonstrate that threats from the deliberate use of chemical weapons remain high and are evolving. One of the deadliest classes of chemical weapons are the organophosphorus nerve agents. It is now clear that both state and non-state actors have the ability to deploy and use these types of weapons against individuals and the wider civilian population posing a real and significant threat. The objective of this article is to provide an overview of the issues impacting on a timely critical response to the accidental or deliberate release of Organophosphorus Nerve Agents in order to enhance the understanding of their effects and provide guidance on how first responders might better treat themselves or victims of exposure through a discussion of available evidence and best practices for rapid skin decontamination. The article also examines use of the current nomenclature of 'wet' and 'dry' to describe different forms of decontamination. One of the key conclusions of this article is that adequate preparedness is essential to ensuring that responders are trained to understand the threat posed by Organophosphorus Nerve Agents as well as how to approach a contaminated environment. A key aspect to achieving this will be to ensure that generic medical countermeasures are forward-deployed and available, preferably within minutes of a contamination and that first responders know how to use them.


Mercury and other metals in feathers of common eider (Somateria mollissima) and tufted puffin (Fratercula cirrhata) from the Aleutian chain of Alaska.
We analyzed arsenic, cadmium, chromium, lead, manganese, mercury, and selenium in the feathers of common eiders (Somateria mollissima) and tufted puffins (Fratercula cirrhata) from Amchitka and Kiska islands (Aleutians). Between species, puffins had 10 times higher chromium (arithmetic mean = 1820 ppb), 7.5 times higher selenium (mean = 6600 ppb), and 3 times higher mercury (mean = 2540 ppb) than eiders. Eiders had significantly higher levels of manganese than puffins. Puffins are higher on the food chain than eiders, which is reflected in their generally higher levels of metals in their feathers. Interisland differences were generally small, and there were few significant differences as a function of the three nuclear test locations on Amchitka. The only sex-related difference was that female puffins had higher mercury than males (arithmetic mean of 3060 ppb vs. 2270 ppb). Mean levels of metals in the feathers of puffins and eiders from the Aleutians were low compared with comparable studies elsewhere, and the relatively low levels of metals do not indicate the potential for adverse behavioral or reproductive effects in the birds themselves, nor pose concern for other consumers, including subsistence hunters.


Leptospirosis outbreak following severe flooding: a rapid assessment and mass prophylaxis campaign; Guyana, January-February 2005.
Leptospirosis is a zoonosis usually transmitted through contact with water or soil contaminated with urine from infected animals. Severe flooding can put individuals at greater risk for contracting leptospirosis in endemic areas. Rapid testing for the disease and large-scale interventions are necessary to identify and control infection. We describe a leptospirosis outbreak following severe flooding and a mass chemoprophylaxis campaign in Guyana. From January-March 2005, we collected data on suspected leptospirosis hospitalizations and deaths. Laboratory testing included anti-leptospiral dot enzyme immunoassay (DST), immunohistochemistry (IHC) staining, and microscopic agglutination testing (MAT). DST testing was conducted for 105 (44%) of 236 patients; 52 (50%) tested positive. Four (57%) paired serum samples tested by MAT were confirmed leptospirosis. Of 34 total deaths attributed to leptospirosis, postmortem samples from 10 (83%) of 12 patients were positive by IHC. Of 201 patients interviewed, 89% reported direct contact with flood waters. A 3-week doxycycline chemoprophylaxis campaign reached over 280,000 people. A confirmed leptospirosis outbreak in Guyana occurred after severe flooding, resulting in a massive chemoprophylaxis campaign to try to limit morbidity and mortality.


Cardiac computed tomography in patients with acute chest pain.
The efficient and reliable evaluation of patients with acute chest pain is one of the most challenging tasks in the emergency department. Coronary computed tomography (CT) angiography may play a major role, since it permits ruling out coronary artery disease with high accuracy if performed with expertise in properly selected and prepared patients. Several randomized trials have established early cardiac CT as a viable safe and potentially more efficient alternative to functional testing in the evaluation of acute chest pain. Ongoing investigations explore whether advanced anatomic and functional assessments such as high-risk coronary plaque, resting myocardial perfusion, and left ventricular function, or the simulation of the fractional coronary flow reserve will add information to the anatomic assessment for stenosis, which would allow expanding the benefits of cardiac CT from triage to treatment decisions. Especially, the combination of high-sensitive troponins and coronary computed tomography angiography may play a valuable role in future strategies for the management of patients presenting with acute chest pain.


[Factors determining the breastfeeding in children attending public and not-for-profit daycare centers in São Paulo, Brazil].
Cross-sectional study with 270 children and their mothers in eight public and philanthropic daycare centers in the city of São Paulo, Brazil. The objective is to identify the determinants of exclusive breastfeeding (EBF) and breastfeeding (BF). The Mann-Whitney/ Wilcoxon test and survival analysis; Kaplan Meier curves and Cox multiple regression models were used for statistical analyses. The median of exclusive breastfeeding duration was 79.1 +/- 55.6 days and breastfeeding was 185.3 +/- 174.2 days. In multivariate analysis, the following risk factors of early weaning for exclusive breastfeeding were identified: pacifier use (HR = 1.65, 95% CI = 1.24 to 2.2); previous hospital admission (HR = 1.35, 95% CI = 1.01 to 1.80); mother working outside home (HR = 1.33, 95% CI = 1.00 to 1.76). For breastfeeding were identified: pacifier use (HR = 2.54, 95% CI = 1.87 to 3.45) and mother who works outside the home (HR = 1.51, 95% CI = 1.14-1.99). The results show that it is necessary to continue to promote and support breastfeeding, mainly the exclusive breastfeeding until six months of age. The daycare centers should incorporate this idea, once they may have direct control over some of the early weaning determinants, and are also good places to deliver messages and guidance on nutrition education to mothers and caregivers in contact with children under three years old.


Optimizing survival outcomes for adult patients with nontraumatic cardiac arrest [digest].
Patient survival after cardiac arrest can be improved significantly with prompt and effective resuscitative care. This systematic review analyzes the basic life support factors that improve survival outcome, including chest compression technique and rapid defibrillation of shockable rhythms. For patients who are successfully resuscitated, comprehensive postresuscitation care is essential. Targeted temperature management is recommended for all patients who remain comatose, in addition to careful monitoring of oxygenation, hemodynamics, and cardiac rhythm. Management of cardiac arrest in circumstances such as pregnancy, pulmonary embolism, opioid overdose and other toxicologic causes, hypothermia, and coronary ischemia are also reviewed. [Points & Pearls is a digest of Emergency Medicine Practice].


Point of care SARS-CoV-2 nucleic acid testing in schools improves school attendance.
Background: National lockdowns have led to significant interruption to children's education globally. In the Autumn term in 2020, school absence in England and Wales was almost five times higher than the same period in 2019. Transmission of SARS-CoV-2 in schools and ongoing interruption to education remains a concern. However, evaluation of rapid point of care (POC) polymerase chain reaction (PCR) testing in British schools has not been undertaken. Methods: This is a survey of secondary schools in England that implemented PCR-based rapid POC testing. The study aims to measure the prevalence of SARS-CoV-2 infection in schools, to assess the impact of this testing on school attendance and closures, and to describe schools experiences with testing. All schools utilised the SAMBA II SARS-CoV-2 testing platform. Results: 12 fee-paying secondary schools in England were included. Between September 1 st 2020 and December 16 th 2020, 697 on site rapid POC PCR tests were performed and 6.7% of these were positive for SARS-CoV-2 infection. There were five outbreaks in three schools during this time which were contained. Seven groups of close contacts within the school known as bubbles had to quarantine but there were no school closures. 84% of those tested were absent from school for less than one day whilst awaiting their test result. This potentially saved between 1047 and 1570 days off school in those testing negative compared to the NHS PCR laboratory test. Schools reported a positive impact of having a rapid testing platform as it allowed them to function as fully as possible during this pandemic. Conclusions: Rapid POC PCR testing platforms should be widely available and utilised in school settings. Reliable positive tests will prevent outbreaks and uncontrolled spread of infection within school settings. Reliable negative test results will reassure students, parents and staff and prevent disruption to education.


Spatial attention modulates visual gamma oscillations across the human ventral stream.
Oscillatory synchronization in the gamma frequency range has been proposed as a neuronal mechanism to prioritize processing of relevant stimuli over competing ones. Recent studies in animals found that selective spatial attention enhanced gamma-band synchronization in high-order visual areas (V4) and increased the gamma peak frequency in V1. The existence of such mechanisms in the human visual system is yet to be fully demonstrated. In this study, we used MEG, in combination with an optimised stimulus design, to record visual gamma oscillations from human early visual cortex, while participants performed a visuospatial attention cueing task. First, we reconstructed virtual sensors in V1/V2, where gamma oscillations were strongly induced by visual stimulation alone. Second, following the results of a statistical comparison between conditions of attention, we reconstructed cortical activity also in inferior occipital-temporal regions (V4). The results indicated that gamma amplitude was modulated by spatial attention across the cortical hierarchy, both in the early visual cortex and in higher-order regions of the ventral visual pathway. In contrast, we found no evidence for an increase in the gamma peak frequency in V1/V2 with attention. The gamma response tended to peak earlier in V1/V2 than in V4 by approximately 70 ms, consistent with a feed-forward role of gamma-band activity in propagating sensory representations across the visual cortical hierarchy. Together, these findings suggest that differences in experimental design or methodology can account for the inconsistencies in previous animal and human studies. Furthermore, our results are in line with the hypothesis of enhanced gamma-band synchronization as an attentional mechanism in the human visual cortex.


Interactive iBook-Based Patient Education in a NeuroTrauma Clinic.
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Educational interventions may alleviate the burden of TBI for patients and their families. Interactive modalities that involve engagement with the educational material may enhance patient knowledge acquisition when compared to static text-based educational material. To determine the effects of educational interventions in the outpatient setting on self-reported patient knowledge, with a focus on iPad-based (Apple, Cupertino, California) interactive modules. Patients and family members presenting to a NeuroTrauma clinic at a tertiary care academic medical center completed a presurvey assessing baseline knowledge of TBI or concussion, depending on the diagnosis. Subjects then received either an interactive iBook (Apple) on TBI or concussion, or an informative pamphlet with identical information in text format. Subjects then completed a postsurvey prior to seeing the neurosurgeon. All subjects (n = 152) significantly improved on self-reported knowledge measures following administration of either an iBook (Apple) or pamphlet (P < .01, 95% confidence interval [CI]). Subjects receiving the iBook (n = 122) performed significantly better on the postsurvey (P < .01, 95% CI), despite equivalent presurvey scores, when compared to those receiving pamphlets (n = 30). Lastly, patients preferred the iBook to pamphlets (P < .01, 95% CI). Educational interventions in the outpatient NeuroTrauma setting led to significant improvement in self-reported measures of patient and family knowledge. This improved understanding may increase compliance with the neurosurgeon's recommendations and may help reduce the potential anxiety and complications that arise following a TBI.


Preparedness of Ob/Gyn residents for fellowship training in gynecologic oncology.
Residency training in obstetrics and gynecology is being challenged by increasingly stringent regulations and decreased operative experience. We sought to determine the perception of preparedness of incoming gynecologic oncology fellows for advanced surgical training in gynecologic oncology. An online survey was sent to gynecologic oncologists involved in fellowship training in the United States. They were asked to evaluate their most recent incoming clinical fellows in the domains of professionalism, level of independence/graduated responsibility, psychomotor ability, clinical evaluation and management, and academia and scholarship using a standard Likert-style scale. The response rate among attending physicians was 40% (n = 105/260) and 61% (n = 28/46) for program directors. Of those who participated, 49% reported that their incoming fellows could not independently perform a hysterectomy, 59% reported that they could not independently perform 30 min of a major procedure, 40% reported that they could not control bleeding, 40% reported that they could not recognize anatomy and tissue planes, and 58% reported that they could not dissect tissue planes. Fellows lacked an understanding of pathophysiology, treatment recommendations, and the ability to identify and treat critically ill patients. In the academic domain, respondents agreed that fellows were deficient in the areas of protocol design (54%), statistical analysis (54%), and manuscript writing (65%). These results suggest that general Ob/Gyn residency is ineffective in preparing fellows for advanced training in gynecologic oncology and should prompt a revision of the goals and objectives of resident education to correct these deficiencies.


The Anti-osteoporosis Effects of Natto on Bone Mineral Density in Perimenopausal Women.
Objective and Aims: This study aims to conduct a systematic review and meta-analysis for prospective studies to investigate the improvement effects of natto on bone mineral density (BMD) in perimenopausal women. PubMed, EMBASE and Cochrane database searched upto February 2019. This study was carried out according to the PRISMA guidelines10 for systematic reviews. The protocol of the review was registered in the PROSPERO registry (CRD42019133183). The review identified 3 unique prospective studies comprising 1658 non-overlapping participants. Meta-analysis showed that natto could significantly improve lumbar bone mineral density (BMD) (P=0.002, WMD=0.26; 95% CI:0.09-0.43) in cohort studies. However, the randomized controlled study showed no statistical difference between the two (P=0.31, WMD=0.05; 95% CI:- 0.05-0.15). In addition, natto significantly improved the BMD of the femoral neck in a cohort study and randomized control study (P=0.03, WMD=0.42). 95% CI:0.05-0.79, I2= 72%); (P < 0.0001, WMD=0.16; 95% CI:0.08-0.24), respectively. However, all studies demonstrated that natto has no improvement effects on a hip joint (BMD). In that, the cohort study showed no statistical significance between the natto intake group and the control group (P=0.21, WMD=0.10). 95% CI:-0.06-0.25, I2= 18%) and the randomized controlled study also showed no statistical significance between the natto intake group and the control group (P=0.09, WMD=-0.06). 95% CI:-0.13- 0.01). Through our current systematic review and meta-analyize of these prosepctive studies of natto's anti-osteoporostic effecs on BMD, we found that the dietary intake of natto demonstrated a improving effects on the BMD of the femoral neck, but has no effects on the hip joint. Such interesting results may be related to the differences between anatomical structure between various tissues. Besides that, the results of the RCT study and cohort study on the lumbar spine were not the same, which may be related to the fact that participants in the RCT study were Caucasian and participants in the cohort study were Asian. Therefore, more large-sample and high-quality RCT studies are needed to further clarify the improvement effect of natto on osteoporosis.


Authorship. International Academy of Nursing Editors.
There are no binding or universally accepted rules to answer the questions who is an author and in collaborative works, how should the order of authorship be decided? What follows is a response to those questions in the form of a position paper which was endorsed by editors attending the 1993 InANE conference in Edmonton, Alberta, Canada.


The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter.
The orphan cotransport protein expressed by the SLC5A8 gene has been shown to play a role in controlling the growth of colon cancers, and the silencing of this gene is a common and early event in human colon neoplasia. We expressed this protein in Xenopus laevis oocytes and have found that it transports small monocarboxylic acids. The electrogenic activity of the cotransporter, which we have named SMCT (sodium monocarboxylate transporter), was dependent on external Na(+) and was compatible with a 3 : 1 stoichiometry between Na(+) and monocarboxylates. A portion of the SMCT-mediated current was also Cl(-) dependent, but Cl(-) was not cotransported. SMCT transports a variety of monocarboxylates (similar to unrelated monocarboxylate transport proteins) and most transported monocarboxylates demonstrated K(m) values near 100 microm, apart from acetate and d-lactate, for which the protein showed less affinity. SMCT was strongly inhibited by 1 mm probenecid or ibuprofen. In the absence of external substrate, a Na(+)-independent leak current was also observed to pass through SMCT. SMCT activity was strongly inhibited after prolonged exposure to high external concentrations of monocarboxylates. The transport of monocarboxylates in anionic form was confirmed by the observation of a concomitant alkalinization of the cytosol. SMCT, being expressed in colon and kidney, represents a novel means by which Na(+), short-chain fatty acids and other monocarboxylates are transported in these tissues. The significance of a Na(+)-monocarboxylate transporter to colon cancer presumably stems from the transport of butyrate, which is well known for having anti-proliferative and apoptosis-inducing activity in colon epithelial cells.


Liver protein and metabolite biolabels reveal hepatoprotective effects and active compounds of Eucommiae folium: Exploration of new application of herb based on multi-omics and bioinformatics.
A biolabel-led research based on multi-omics and bioinformatics was applied to analyze the application value of Eucommiae folium (EF) in liver cirrhosis, as well as the mechanism of action and material basis. Multi-omics were used to analyze the biolabels and key pathways of EF intervention in liver tissue. Subsequently, based on the information, bioinformatics was used to analyze the application value of EF in liver disease, as well the mechanism of action and material basis. Finally, histopathological and target expression analyses in an animal model were used to verify biolabels analysis results. Multi-omics showed that 18 proteins and 10 metabolites involved in five key pathways were screened as biolabels. Bioinformatics suggested that the application value of EF for liver cirrhosis may be the highest among the liver diseases that it may treat. Additionally, EF and five active compounds (curcumol, eucalyptol, (+)-catechin, naringenin, and quercetin) may protect the cirrhotic liver against the excessive energy expenditure and hepatic stellate cells activation through suppressing the oxidative phosphorylation pathway in a CCl4-induced mouse model. This study provides reference and evidence for the application value of EF in liver diseases, especially liver cirrhosis.


Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice.
We have recently disrupted Slc12a2, the gene encoding the secretory Na-K-2Cl cotransporter in mice (NKCC1) (Delpire et al., 1999). Gramicidin perforated-patch and whole-cell recordings were performed to study GABA-induced currents in dorsal root ganglion (DRG) neurons isolated from wild-type and homozygote NKCC1 knock-out mice. In wild-type DRG neurons, strong GABA-evoked inward current was observed at the resting membrane potential, suggesting active accumulation of Cl(-) in these cells. This GABA-induced current was blocked by picrotoxin, a GABA(A) receptor blocker. The strong Cl(-) accumulation that gives rise to depolarizing GABA responses is caused by Na-K-2Cl cotransport because reduction of external Cl(-) or application of bumetanide induced a decrease in [Cl(-)](i), whereas an increase in external K(+) caused an apparent [Cl(-)](i) accumulation. In contrast to control neurons, little or no net current was observed at the resting membrane potential in homozygote NKCC1 mutant DRG neurons. E(GABA) was significantly more negative, demonstrating the absence of Cl(-) accumulation in these cells. Application of bumetanide induced a positive shift of E(GABA), suggesting the presence of an outward Cl(-) transport mechanism. In agreement with an absence of GABA depolarization in DRG neurons, behavioral analysis revealed significant alterations in locomotion and pain perception in the knock-out mouse. Our results clearly demonstrate that the Na-K-2Cl cotransporter is responsible for [Cl(-)](i) accumulation in DRG neurons and that via regulation of intracellular Cl(-), the Na-K-2Cl cotransporter participates in the modulation of GABA neurotransmission and sensory perception.


Stable dynamic detection scheme for magnetostrictive fiber-optic interferometric sensors.
A stable dynamic detection scheme for magnetostrictive fiber-optic interferometric sensors is studied. The working principle is presented and the experimental verification is performed. The results show that the system employing the dynamic detection scheme has better stability and sensitivity in comparison with the system employing quadrature control technique.


Tuning of spectral and angular distribution of scattering from single gold nanoparticles by subwavelength interference layers.
Localized surface plasmon resonance (LSPR) as the resonant oscillation of conduction electrons in metal nanostructures upon light irradiation is widely used for sensing as well as nanoscale manipulation. The spectral resonance band position can be controlled mainly by nanoparticle composition, size, and geometry and is slightly influenced by the local refractive index of the near-field environment. Here we introduce another approach for tuning, based on interference modulation of the light scattered by the nanostructure. Thereby, the incoming electric field is wavelength-dependent modulated in strength and direction by interference due to a subwavelength spacer layer between nanoparticle and a gold film. Hence, the wavelength of the scattering maximum is tuned with respect to the original nanoparticle LSPR. The scattering wavelength can be adjusted by a metallic mirror layer located 100-200 nm away from the nanoparticle, in contrast to near-field gap mode techniques that work at distances up to 50 nm in the nanoparticle environment. Thereby we demonstrate, for the first time at the single nanoparticle level, that dependent on the interference spacer layer thickness, different distributions of the scattered signal can be observed, such as bell-shaped or doughnut-shaped point spread functions (PSF). The tuning effect by interference is furthermore applied to anisotropic particles (dimers), which exhibit more than one resonance peak, and to particles which are moved from air into the polymeric spacer layer to study the influence of the distance to the gold film in combination with a change of the surrounding refractive index.


ESX-3 secretion system in Mycobacterium: An overview.
Mycobacteria are microorganisms distributed in the environment worldwide, and some of them, such as Mycobacterium tuberculosis or M. leprae, are pathogenic. The hydrophobic mycobacterial cell envelope has low permeation and bacteria need to export products across their structure. Mycobacteria possess specialized protein secretion systems, such as the Early Secretory Antigenic Target 6 secretion (ESX) system. Five ESX loci have been described in M. tuberculosis, called ESX-1 to ESX-5. The ESX-3 secretion system has been associated with mycobacterial metabolism and growth. The locus of this system is highly conserved across mycobacterial species. Metallo-proteins regulate negative ESX-3 transcription in high conditions of iron and zinc. Moreover, this secretion system is part of an antioxidant regulatory pathway linked to Zinc. EccA3, EccB3, EccC3, EccD3, and EccE3 are components of the ESX-3 secretion machinery, whereas EsxG-EsxH, PE5-PPE4, and PE15-PPE20 are proteins secreted by this system. In addition, EspG3 and MycP3 are complementary proteins involved in transport and proteolysis respectively. This system is associated to mycobacterial virulence by releasing the bacteria from the phagosome and inhibiting endomembrane damage response. Furthermore, components of this system inhibit the host immune response by reducing the recognition of M. tuberculosis-infected cells. The components of the ESX-3 secretion system play a role in drug resistance and cell wall integrity. Moreover, the expression data of this system indicated that external and internal factors affect ESX-3 locus expression. This review provides an overview of new findings on the ESX-3 secretion system, its regulation, expression, and functions.


Putting ifs to work: goal-based relevance in conditional directives.
Conditional directives are used by speakers to instruct hearers which actions are to be taken should certain events occur. The authors demonstrate that conditional directives are distinct from indicative conditionals in which speakers predict what is likely to be observed should certain events occur. The 1st set of experiments shows that goal structure determines what information speakers will select to test whether conditional directives have been followed but that these selections do not reflect their interpretations of the deontic necessity and sufficiency of the conditional relation. The 2nd set of experiments shows that formulations of conditional directives differ in how clearly speakers consider them to express their situation-specific intentions and that hearers accurately perceive what speakers intend them to do as a result of these formulations. The authors' findings illustrate a form of social rationality common in everyday interaction, which broadens normative conceptions of conditionals.


Bipolaris fujianensis sp. nov., an emerging pathogen of saplings shoot blight on Chinese fir and its sensitivity to fungicides.
Chinese fir is an extremely important economic tree species in southern China. In recent years, 74.5% of Chinese fir saplings suffered from shoot blight in Shunchang County, Nanping City, Fujian province, China. Seventeen isolates were collected from rotten shoots, and their pathogenicity was confirmed following Koch's postulate. The five pathogenic isolates were identified as genus Bipolaris based on morphological characteristics, including septate and geniculate conidiophores, conidiogenous nodes smooth to slightly verruculose, dematiaceous phragmospore conidia, oblong or fusiform conidia, and slightly protruding or truncate hilum on conidia, but number of pseudosepta (3 to 11, most 5 to 8) and size of conidia (22.81 to 116.13) μm × (9.16 to 26.58) μm are different from the known species of Bipolaris. A phylogenetic analysis based on ITS, GAPDH and Tef1-α sequences determined that the five strains belong to a new species of Bipolaris and the name Bipolaris fujianensis sp. nov. is proposed. The fungicide sensitivity of the pathogen strain Cfsb3 was further evaluated using eight fungicides. Flusilazole, difenoconazole, tebuconazole and propiconazole exhibited high toxicity to Cfsb3, the effective concentration inhibiting 50% (EC50) of mycelial growth were 0.08, 0.20, 0.34 and 0.36 μg/ml, respectively, for these four fungicides. Flusilazole, difenoconazole and iprodione inhibited B. fujianensis by 100% on detached Chinese fir shoots at their recommended concentrations, but azoxystrobin and thiram were ineffective. In conclusion, this study reported an emerging pathogen of Chinese fir sapling shoot blight and proposed triazole and dicarboximidies fungicides for this disease control.


[Myeloma bone disease].
Multiple myeloma (MM) develops and expands almost exclusively in the bone marrow, and generates devastating bone destruction. MM cells produce a variety of cytokines to stimulate RANK ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. Pim-2 kinase as well as growth factor independence-1 (Gfi-1) were found to be up-regulated in bone marrow stromal cells by major inhibitors of bone formation known in myeloma as common downstream mediators for the suppression of osteoblastogenesis. The biology of osteocytes is largely unknown in myeloma bone lesions, but the reduction of viable osteocytes and their correlation with osteoclastogenesis have been demonstrated.