bluuebunny/crossref_metadata_2025 huggingface dataset:
‘All theKing's horses …’: the problematical fate of born‐again evidence‐based medicine: commentary onGreenhalgh,T.,Snow,R.,Ryan,S.,Rees,S., andSalisbury,H. (2015) six ‘biases’ against patients and carers in evidence‐based medicine.BioMedCentralMedicine, 13:200
Authors: Wyer Peter , Alves da Silva Suzana
Published: December 2015

The phrase ‘evidence‐based medicine (EBM)' is being used by bothEBMadvocates and adversaries to broadly denote the production and use of clinical research throughout the healthcare system. Recently, this trend was joined by a call for a general expansion and rebirth ofEBMto encompass a diverse range of healthcare activities otherwise corresponding to person‐centred care. The call asserts thatEBMis to blame for anti‐patient biases within clinical practice and in policy and public health domains. Effective critique of eitherEBMor of the healthcare system requires thatEBMitself be properly identified as a research literacy movement that grew out of clinical epidemiology of the 1970's and 1980's. We demonstrate the ineffectiveness of inappropriately targeted critiques of healthcare under the banner of born‐againEBM. We identify the strengths and weaknesses ofEBMas an educational movement drawing on the concept of literacy associated with the Brazilian educator Paolo Freire. We consider the relationship ofEBMto clinical epidemiology and conclude that it cannot fruitfully divorce itself from the latter. We briefly consider existing precedents for philosophically sound conceptual platforms for advocacy of person‐centred healthcare and broad based critique of the healthcare system including relationship‐centred care. We conclude that traditionalEBM, as a framework for research literacy training of both clinicians and policy makers, must continue to play a subsidiary role within an expanding patient‐centred healthcare system and that advocacy efforts on behalf of patient voice and engagement are best pursued unencumbered by subsidiary agendas.
Suppression of colitis‐associated carcinogenesis through modulation of IL‐6/STAT3 pathway by balsalazide and VSL#3
Authors: Do Eun‐ju , Hwang Sung Wook , Kim Sang‐Yeob , Ryu Yeon‐Mi , Cho Eun A. , Chung Eun‐Ju , Park Sunha , Lee Hyo Jeong , Byeon Jeong‐Sik , Ye Byong Duk , Yang Dong‐Hoon , Park Sang Hyoung , Yang Suk‐Kyun , Kim Jin‐Ho , Myung Seung‐Jae
Published: December 2015

Background and Aim

Recent studies suggest that the anti‐inflammatory agent balsalazide (BSZ) and probiotic agent VSL#3 have potential therapeutic benefits for the treatment of patients with inflammatory bowel disease. However, their effectiveness in preventing colitis‐associated carcinogenesis (CAC) remains uncertain. The aim of the present study was to determine the chemopreventive effects of BSZ and VSL#3 in the murine azoxymethane (AOM)/dextran sodium sulfate (DSS) model.

Methods

C57B/L6J mice were randomly divided into four groups: CAC group, BSZ group, VSL#3 group, and BSZ + VSL#3 group. After 2 weeks, the AOM/DSS model was induced by AOM injection followed by two cycles of 2% DSS.

Results

During first and second cycles of DSS, the number of F4/80‐positive macrophages was significantly lower in the drug‐treated groups compared with the CAC group (P < 0.05). At the endpoint, the total numbers of tumors in the drug‐treated groups were significantly low compared with the CAC group (P < 0.05), and the drug‐treated groups had significantly lower F4/80‐positive macrophages in the tumor stroma (P < 0.01). The protein production of macrophage inflammatory protein 1 beta, monocyte chemoattractant protein‐1, interleukin (IL)‐6, and IL‐10 in the colon tissues decreased in concordance with the plasma concentrations of the cytokines (P < 0.05). The drug‐treated groups revealed lower expression of p‐STAT3 compared with the CAC group. In addition, BCL2 decreased, and BAX increased markedly in the BSZ + VSL#3 group.

Conclusions

These results revealed that BSZ and VSL#3 have chemopreventive effects against CAC through IL‐6/STAT3 suppression. BSZ and VSL#3 could be suitable options for chemoprevention of colorectal cancer.
STATED PREFERENCES FOR PUBLIC SERVICES: A CLASSIFICATION AND SURVEY OF APPROACHES
Authors: Schläpfer Felix
Published: December 2015

The wider range of stated preference approaches to value public goods has not been systematically reviewed in recent years. The objective of this paper is to provide an overview of this literature and to evaluate the strengths and limitations of alternative approaches. Since the public referendum has served as a ‘blueprint’ for survey design, two key dimensions by which many surveys differ from the public referendum are used for a simple classification of approaches. This yields eleven approaches, including different variants of micro‐based demand surveys, referendum surveys, budget allocation surveys and contingent valuation surveys. Their evaluation in terms of the preference information they produce and the assumptions they require suggests there is no single preferred approach. Instead, each approach has its characteristic profile of strengths and limitations which follow from how it strikes the balance between the conflicting goals of measuring entire willingness‐to‐pay distributions and presenting manageable, credible and incentive compatible questions. Ultimately, judgments about the suitability of alternative approaches for specific objectives should rely on empirical evidence. Progress in the field could greatly benefit from a routine implementation of powerful experimental validity tests in applied work.
Parental Divorce, Residence Arrangements, and Contact Between Grandchildren and Grandparents
Authors: Jappens Maaike , Van Bavel Jan
Published: December 2015

When parents divorce, grandparents can play a supportive role in the lives of their grandchildren, but a parental divorce may also put grandchild–grandparent ties under pressure. In this study the authors investigated how grandchildren of married and divorced parents differ in the frequency of face‐to‐face contacts with grandparents and how this is mediated by postdivorce residence arrangements. Based on the multi‐actor survey “Divorce in Flanders,” they used reports of contact provided by more than 1,000 grandchildren and compared them with more than 1,100 grandparent reports for validation. The results showed that grandchildren from divorced parents have fewer contacts with their grandparents than grandchildren whose parents are married but that it is the postdivorce residence arrangement of grandchildren that produces this result. When grandchildren live with their divorced father or in a shared residence arrangement, they even see paternal grandparents more often than grandchildren with married parents.
Pattern of galectins expression in actinic cheilitis with different risks of malignant transformation
Authors: Lopes Maria Luiza Diniz de Sousa , Nonaka Cassiano Francisco Weege , Queiroz Lélia Maria Guedes , de Souza Lélia Batista , Miguel Márcia Cristina da Costa , da Silveira Éricka Janine Dantas
Published: December 2015

Background

Actinic cheilitis (AC) is a chronic inflammatory lesion that in some situations can turn into squamous cell carcinoma of the lip. The molecular mechanisms involved in this process are not yet completely understood. This study aimed to investigate the expression pattern of galectins in actinic cheilitis according to the histopathological grading.

Methods

Immunoexpression of galectin‐1, galectin‐3, galectin‐7, and galectin‐9 was semiquantitatively analyzed in 65 cases of actinic cheilitis graded as low risk (n = 40) or high risk (n = 25) of malignant transformation. Association between the location of the galectins in the cellular compartments and histopathological grading was analyzed.

Results

Galectin‐1 was mainly observed in the cell cytoplasm, and was elevated (score 3) in 60% of cases, regardless of the histopathological grade (P > 0.05). Galectin‐3 expression was higher in high‐risk group than in the low‐risk group (P < 0.05), with a predominant expression in the cytoplasm and nucleus of low‐risk (67.5%), and only in the cytoplasm of high‐risk cases (60%) (P < 0.05). Galectin‐7 expression did not show significant differences between low‐risk and high‐risk groups (P > 0.05). With respect to galectin‐9, 89.2% of cases were positive, showing decrease in median of scores as there was an increase in histological grade (P < 0.001), with predominant expression in the nucleus and cytoplasm.

Conclusions

This study is the first indication of galectins involvement in the pathogenesis and morphologic progression of actinic cheilitis, particularly galectin‐3 and galectin‐9.
Differences in MYB expression and gene abnormalities further confirm that salivary cribriform basal cell tumors and adenoid cystic carcinoma are two distinct tumor entities
Authors: Tian Zhen , Li Lei , Zhang Chun‐ye , Gu Ting , Li Jiang
Published: December 2015

Background

In practices, some cases of salivary basal cell tumors that consist mainly of cribriform growth pattern are difficult to differentiate from adenoid cystic carcinoma (AdCC). Identification of reliable molecular biomarkers for the differential diagnosis between them is required.

Methods

Twenty‐two cases of cribriform salivary basal cell tumors (at least 10% cribriform pattern present in each tumor) comprising 18 cases of basal cell adenoma (BCA) and four cases of basal cell adenocarcinoma (BcAC) were collected between 1985 and 2008. Twenty cases of cribriform AdCC were retrieved from our archives. MYB protein expression and gene abnormalities were detected in all cases by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) analyses, respectively.

Results

Neither MYB protein nor split genes were detected in any of the cases of cribriform basal cell tumors, while 55% (11/20) of cases of cribriform AdCC had MYB protein expression. High MYB expression was detected in 81.8% (9/11) cases, while low expression was found in the remaining cases. FISH analysis indicated that nine AdCC tumors with high MYB protein expression were split gene‐positive, while MYB gene splitting was not detected in the 11 cases with low or absent MYB protein expression.

Conclusion

The molecular changes in AdCC differ from those associated with cribriform basal cell tumors, which further confirms that cribriform basal cell tumors and AdCC are two distinct tumor entities. Simultaneous detection of MYB protein expression and the associated molecular changes could be beneficial in differentiating salivary cribriform basal cell tumors from AdCC.
Refined assessment of the geographic distribution of Geoffroy's cat (Leopardus geoffroyi) (Mammalia: Felidae) in the Neotropics
Authors: Cuyckens G. A. E. , Pereira J. A. , Trigo T. C. , Da Silva M. , Gonçalves L. , Huaranca J. C. , Bou Pérez N. , Cartes J. L. , Eizirik E.
Published: December 2015

Understanding the fine‐scale geographic distribution of a species has applications in biogeography, ecology, evolution and conservation. Species distribution models (SDM) have been widely used to predict geographic and climatic ranges of species. Geoffroy's cat Leopardus geoffroyi is a small felid of least concern that occupies a wide variety of habitat types in Argentina, Bolivia, Brazil, Chile, Paraguay and Uruguay. We evaluated the fine‐scale distribution of Geoffroy's cat at the sub‐continental level, estimated its current extent and area of occurrence and discussed the current and potential ranges developed with SDM. On the basis of species occurrences (n = 1502) and large‐scale environmental data, two model types (‘environmental’ and ‘land cover’) were developed using MaxEnt. The estimated extent of occurrence of Geoffroy's cat was 3 180 664 km2, but the potential area of occurrence predicted by our environmental model was 70% larger due to areas with high suitability (i.e. >0.5) compared to the species’ current range. The most important bioclimatic factors affecting Geoffroy's cat presence were temperature seasonality, mean temperature of the coldest quarter and annual precipitation. Two recent records obtained outside the known distribution of the species fell within the high‐suitability area (i.e. >0.5) predicted by our model. Our SDM suggest that this habitat‐generalist felid is probably expanding its distribution range by taking advantage of changes in human land use.
Performance of non‐invasive models of fibrosis in predicting mild to moderate fibrosis in patients with non‐alcoholic fatty liver disease
Authors: Siddiqui Mohammad S. , Patidar Kavish R. , Boyett Sherry , Luketic Velimir A. , Puri Puneet , Sanyal Arun J.
Published: December 2015

Background & Aims

In non‐alcoholic fatty liver disease, presence of fibrosis is predictive of long‐term liver–related complications. Currently, there are no reliable and non‐invasive means of quantifying fibrosis in those with non‐alcoholic fatty liver disease. Therefore, we aimed to evaluate the performance of a panel of non‐invasive models in predicting fibrosis in non‐alcoholic fatty liver disease.

Methods

The accuracy of FibroMeter non‐alcoholic fatty liver disease, fibrosis 4 and four other non‐invasive models in predicting fibrosis in those with biopsy proven non‐alcoholic fatty liver disease was compared. These models were constructed post hoc in patients who had necessary clinical information collected within 2 months of a liver biopsy. The areas under receiver operating characteristics curves were compared for each model using Delong analysis. Optimum cut‐off for each model and fibrosis stage were calculated using the Youden index.

Results

The area under receiver operating characteristics curves for F ≥ 1 fibrosis for fibrosis 4 and FibroMeter non‐alcoholic fatty liver disease was 0.821 and 0.801 respectively. For F ≥ 3, the area under receiver operating characteristics curves was 0.866 for fibrosis 4 and 0.862 for FibroMeter non‐alcoholic fatty liver disease. Delong analysis showed the area under receiver operating characteristics curves was statistically different for fibrosis 4 and FibroMeter non‐alcoholic fatty liver disease compared with BARD, BAAT and aspartate aminotransferase:alanine aminotransferase ratio for F ≥ 1 and F ≥ 3. Area under receiver operating characteristics curves were significantly different for fibrosis 4 and FibroMeter non‐alcoholic fatty liver disease for F ≥ 3 compared with non‐alcoholic fatty liver disease fibrosis score. At a fixed sensitivity of 90%, FibroMeter non‐alcoholic fatty liver disease had the highest specificity for F ≥ 1 (52.4%) and F ≥ 3 (63.8%). In contrast, at a fixed specificity of 90%, fibrosis 4 outperformed other models with a sensitivity of 60.2% for F ≥ 1 and 70.6% for F ≥ 3 fibrosis.

Conclusion

These non‐invasive models of fibrosis can predict varying degrees of fibrosis from routinely collected clinical information in non‐alcoholic fatty liver disease.
Ribosome‐associated pentatricopeptide repeat proteins function as translational activators in mitochondria of trypanosomes
Authors: Aphasizheva Inna , Maslov Dmitri A. , Qian Yu , Huang Lan , Wang Qi , Costello Catherine E. , Aphasizhev Ruslan
Published: December 2015

Mitochondrial ribosomes of Trypanosoma brucei are composed of 9S and 12S rRNAs, eubacterial‐type ribosomal proteins, polypeptides lacking discernible motifs and approximately 20 pentatricopeptide repeat (PPR) RNA binding proteins. Several PPRs also populate the polyadenylation complex; among these, KPAF1 and KPAF2 function as general mRNA 3′ adenylation/uridylation factors. The A/U‐tail enables mRNA binding to the small ribosomal subunit and is essential for translation. The presence of A/U‐tail also correlates with requirement for translation of certain mRNAs in mammalian and insect parasite stages. Here, we inquired whether additional PPRs activate translation of individual mRNAs. Proteomic analysis identified KRIPP1 and KRIPP8 as components of the small ribosomal subunit in mammalian and insect forms, but also revealed their association with the polyadenylation complex in the latter. RNAi knockdowns demonstrated essential functions of KRIPP1 and KRIPP8 in the actively respiring insect stage, but not in the mammalian stage. In the KRIPP1 knockdown, A/U‐tailed mRNA encoding cytochrome c oxidase subunit 1 declined concomitantly with the de novo synthesis of this subunit whereas polyadenylation and translation of cyb mRNA were unaffected. In contrast, the KRIPP8 knockdown inhibited A/U‐tailing and translation of both CO1 and cyb mRNAs. Our findings indicate that ribosome‐associated PPRs may selectively activate mRNAs for translation.
Transcriptional control of quorum sensing and associated metabolic interactions in Pseudomonas syringae strain B728a
Authors: Scott Russell A. , Lindow Steven E.
Published: December 2015

Pseudomonas syringae pv. syringae cell densities fluctuate regularly during host plant colonization. Previously we identified nine genes dependent on the quorum‐sensing‐associated luxR homolog ahlR during epiphytic and apoplastic stages of host colonization. Yet their contributions to host colonization remain obscure, despite ahlR regulon presence within and beyond the P. syringae pan‐genome. To elucidate AhIR regulon member functions, we characterized their regulation, interactions with each other, and contributions to the metabolome. We report Psyr_1625, encoding a functional pyruvate deydrogenase‐E1 subunit PdhQ, is required to prevent the accumulation of pyruvate in rich media. Furthermore it is exquisitely regulated by both repression of its own promoter by QrpR within a novel clade of the MarR regulator family, and co‐transcription on a 5kb transcript originating from the AhlR‐driven ahlI promoter, that reads over ahlR and qrpR. Metabolites accumulated during expression of the second AhlR‐driven operon (Psyr_1620‐1616, paoABCDE), only in a pdhQ mutant background, in addition to pyruvate, are herein associated with derepression of QrpR‐repressed pdhQ. AHL signaling, QrpR, and transcriptional read‐through events integrate to ensure AHL‐dependent expression of a novel metabolism in anticipation of environmental stress, while minimizing endogenously generated cytotoxicity.
The Legionella pneumophila CpxRA two‐component regulatory system: new insights into CpxR's function as a dual regulator and its connection to the effectors regulatory network
Authors: Feldheim Yaron S. , Zusman Tal , Speiser Yariv , Segal Gil
Published: December 2015

Legionella pneumophila utilizes the Icm/Dot type‐IV secretion system to translocate approximately 300 effector proteins into host cells, and the CpxRA two‐component system (TCS) was previously shown to regulate the expression of several of these effectors. In this study, we expanded the pool of L. pneumophila CpxR‐regulated genes to 38, including 27 effector‐encoding genes. Our study demonstrates for the first time that the CpxR dual regulator has different requirements for activation and repression of target genes. These differences include the positioning of the CpxR regulatory element relative to the promoter element, and the effect of CpxR phosphate donors on the expression of CpxR target genes. In addition, unlike most response regulators, a mutant form of the L. pneumophila CpxR which cannot be phosphorylated was found to self‐interact, and to repress gene expression similarly to wild‐type CpxR, even though its ability to activate gene expression was reduced. Moreover, the CpxRA TCS was found to activate the expression of LetE which was found to function as a connector protein between the CpxRA TCS and the LetAS‐RsmYZ‐CsrA regulatory cascade. Our results show that CpxR plays a major role in L. pneumophila pathogenesis gene expression and functions as part of a regulatory network.
RNase III mediated cleavage of the coding region of mraZ mRNA is required for efficient cell division in Corynebacterium glutamicum
Authors: Maeda Tomoya , Tanaka Yuya , Takemoto Norihiko , Hamamoto Nagisa , Inui Masayuki
Published: December 2015

The Corynebacterium glutamicum R cgR_1959 gene encodes an endoribonuclease of the RNase III family. Deletion mutant of cgR_1959 (Δrnc mutant) showed an elongated cell shape, and presence of several lines on the cell surface, indicating a required of RNase III for maintaining normal cell morphology in C. glutamicum. The level of mraZ mRNA was increased, whereas cgR_1596 mRNA encoding a putative cell wall hydrolase and ftsEX mRNA were decreased in the Δrnc mutant. The half‐life of mraZ mRNA was significantly prolonged in the Δrnc and the Δpnp mutant strains. This indicated that the degradation of mraZ mRNA was performed by RNase III and the 3′‐to‐5′ exoribonuclease, PNPase. Northern hybridization and primer extension analysis revealed that the cleavage site for mraZ mRNA by RNase III is in the coding region. Overproduction of MraZ resulted in an elongated cell shape. The expression of ftsEX decreased while that of cgR_1596 unchanged in an MraZ‐overexpressing strain. An electrophoretic mobility shift assay and a transcriptional reporter assay indicate that MraZ is a transcriptional repressor of ftsEX in C. glutamicum. These results indicate that RNase III is required for efficient expression of MraZ‐dependent ftsEX and MraZ‐independent cgR_1596.
ZAP1‐mediated modulation of triacylglycerol levels in yeast by transcriptional control of mitochondrial fatty acid biosynthesis
Authors: Singh Neelima , Yadav Kamlesh Kumar , Rajasekharan Ram
Published: December 2015

The transcriptional activator Zap1p maintains zinc homeostasis in Saccharomyces cerevisiae. In this study, we examined the role of Zap1p in triacylglycerol (TAG) metabolism. The expression of ETR1 is reduced in zap1Δ. The altered expression of ETR1 results in reduced mitochondrial fatty acid biosynthesis and reduction in lipoic acid content in zap1Δ. The transcription factor Zap1 positively regulates ETR1 expression. Deletion of ETR1 also causes the accumulation of TAG, and the introduction of ETR1 in zap1Δ strain rescues the TAG level. These results demonstrated that the compromised mitochondrial fatty acid biosynthesis causes a reduction in lipoic acid and loss of mitochondrial function in zap1Δ. Functional mitochondria are required for the ATP production and defect in mitochondria slow down the process which may channeled carbon towards lipid biosynthesis and stored in the form of TAG.
Hydrogen sulfide is a novel potential virulence factor of Mycoplasma pneumoniae: characterization of the unusual cysteine desulfurase/desulfhydrase HapE
Authors: Großhennig Stephanie , Ischebeck Till , Gibhardt Johannes , Busse Julia , Feussner Ivo , Stülke Jörg
Published: December 2015

Mycoplasma pneumoniae is a human pathogen causing atypical pneumonia with a minimalized and highly streamlined genome. So far, hydrogen peroxide production, cytadherence, and the ADP‐ribosylating CARDS toxin have been identified as pathogenicity determinants. We have studied haemolysis caused by M. pneumoniae, and discovered that hydrogen peroxide is responsible for the oxidation of heme, but not for lysis of erythrocytes. This feature could be attributed to hydrogen sulfide, a compound that has previously not been identified as virulence factor in lung pathogens. Indeed, we observed hydrogen sulfide production by M. pneumoniae. The search for a hydrogen sulfide‐producing enzyme identified HapE, a protein with similarity to cysteine desulfurases. In contrast to typical cysteine desulfurases, HapE is a bifunctional enzyme: it has both the cysteine desulfurase activity to produce alanine and the cysteine desulfhydrase activity to produce pyruvate and hydrogen sulfide. Experiments with purified HapE showed that the enzymatic activity of the protein is responsible for haemolysis, demonstrating that HapE is a novel potential virulence factor of M. pneumoniae.
Salt‐sensitivity of σH and Spo0A prevents sporulation of Bacillus subtilis at high osmolarity avoiding death during cellular differentiation
Authors: Widderich Nils , Rodrigues Christopher D. A. , Commichau Fabian M. , Fischer Kathleen E. , Ramirez‐Guadiana Fernando H. , Rudner David Z. , Bremer Erhard
Published: December 2015

The spore‐forming bacterium Bacillus subtilis frequently experiences high osmolarity as a result of desiccation in the soil. The formation of a highly desiccation‐resistant endospore might serve as a logical osmostress escape route when vegetative growth is no longer possible. However, sporulation efficiency drastically decreases concomitant with an increase in the external salinity. Fluorescence microscopy of sporulation‐specific promoter fusions to gfp revealed that high salinity blocks entry into the sporulation pathway at a very early stage. Specifically, we show that both Spo0A‐ and SigH‐dependent transcription are impaired. Furthermore, we demonstrate that the association of SigH with core RNA polymerase is reduced under these conditions. Suppressors that modestly increase sporulation efficiency at high salinity map to the coding region of sigH and in the regulatory region of kinA, encoding one the sensor kinases that activates Spo0A. These findings led us to discover that B. subtilis cells that overproduce KinA can bypass the salt‐imposed block in sporulation. Importantly, these cells are impaired in the morphological process of engulfment and late forespore gene expression and frequently undergo lysis. Altogether our data indicate that B. subtilis blocks entry into sporulation in high‐salinity environments preventing commitment to a developmental program that it cannot complete.
A minimized motile machinery for Mycoplasma genitalium
Authors: García‐Morales Luis , González‐González Luis , Querol Enrique , Piñol Jaume
Published: December 2015

The cell wall‐less bacterium Mycoplasma genitalium uses specialized adhesins located at the terminal organelle to adhere to host cells and surfaces. The terminal organelle is a polar structure protruding from the cell body that is internally supported by a cytoskeleton and also has an important role in cell motility. We have engineered a M. genitalium null mutant for MG491 protein showing a massive downstream destabilization of proteins involved in the terminal organelle organization. This mutant strain exhibited striking similarities with the previously isolated MG_218 null mutant strain. Upon introduction of an extra copy of MG_318 gene in both strains, the amount of main adhesins P140 and P110 dramatically increased. These strains were characterized by microcinematography, epifluorescence microscopy and cryo‐electron microcopy, revealing the presence of motile cells and filaments in the absence of many proteins considered essential for cell adhesion and motility. These results indicate that adhesin complexes play a major role in the motile machinery of M. genitalium and demonstrate that the rod element of the cytoskeleton core is not the molecular motor propelling mycoplasma cells. These strains containing a minimized motile machinery also provide a valuable cell model to investigate the adhesion and gliding properties of this human pathogen.
Expression of IroN, the salmochelin siderophore receptor, requires mRNA activation by RyhB small RNA homologues
Authors: Balbontín Roberto , Villagra Nicolás , Pardos de la Gándara Maria , Mora Guido , Figueroa‐Bossi Nara , Bossi Lionello
Published: December 2015

The iroN gene of Salmonella enterica and uropathogenic Escherichia coli encodes the outer membrane receptor of Fe3+‐bound salmochelin, a siderophore tailored to evade capture by the host's immune system. The iroN gene is under negative control of the Fur repressor and transcribed under iron limiting conditions. We show here that transcriptional de‐repression is not sufficient to allow iroN expression, as this also requires activation by either of two partially homologous small RNAs (sRNAs), RyhB1 and RyhB2. The two sRNAs target the same sequence segment approximately in the middle of the 94‐nucleotide 5′ untranslated region (UTR) of iroN mRNA. Several lines of evidence suggest that base pair interaction stimulates iroN mRNA translation. Activation does not result from the disruption of a secondary structure masking the ribosome binding site; rather it involves sequences at the 5′ end of iroN 5′ UTR. In vitro ‘toeprint’ assays revealed that this upstream site binds the 30S ribosomal subunit provided that RyhB1 is paired with the mRNA. Altogether, our data suggest that RyhB1, and to lesser extent RyhB2, activate iroN mRNA translation by promoting entry of the ribosome at an upstream ‘standby’ site. These findings add yet an additional nuance to the polychromatic landscape of sRNA‐mediated regulation.
Clinically silent seizures in a neonate with tuberous sclerosis
Authors: Ikeno Mitsuru , Okumura Akihisa , Abe Shinpei , Igarashi Ayuko , Hisata Ken , Shoji Hiromichi , Shimizu Toshiaki
Published: December 2015

Although seizures during infancy in patients with tuberous sclerosis complex are common, seizures in neonates are infrequent. Here, we report the clinical course and electroencephalography (EEG) findings of a neonate with tuberous sclerosis complex associated with clinically silent seizures. The patient was a girl in whom cardiac tumors were detected on fetal ultrasonography. Brain magnetic resonance imaging during the neonatal period showed subependymal and cortical tubers. Routine EEG indicated unexpected ictal changes with no noticeable clinical symptoms. Ictal EEG was associated with a subtle increase in heart rate and a brief increase in chin electromyogram. These changes were difficult to identify clinically. The patient later developed focal seizures and epileptic spasms and had severe psychomotor delay. The present case suggests the occurrence of clinically silent seizures before the appearance of epileptic spasms in infants with tuberous sclerosis, and that EEG is an option for neonates with a prenatal diagnosis.
Acute oral complications in a pediatric patient with acute lymphoid leukemia
Authors: Kamasaki Yoko , Satoh Kyoko , Nishiguchi Miyuki , Hoshino Tomonori , Fujiwara Taku
Published: December 2015

Pseudomonas aeruginosa is a low‐virulence pathogen that can cause infection in immunocompromised patients. Among pediatric hematologists, it is known that careful attention should be paid to P. aeruginosa as the bacteria responsible for intraoral inflammation, and antibiotic therapy targeting P. aeruginosa is the first‐line treatment during neutropenia in patients with hematological malignancy. Immunosuppressed patients, however, are at high risk of developing inflammation. Here, we report a case involving a 10‐year‐old patient with acute lymphoid leukemia (ALL), in which P. aeruginosa synergistically acted with pre‐existing gingivitis to induce unusual oral necrotic lesions, leading to acute buccal cellulitis and pus discharge from external sinus tracts.
Conceptualizing Social Attention in Developmental Research
Authors: Salley Brenda , Colombo John
Published: December 2015

The term social attention has become widely used during the last decade, appearing within behavioral neuroscience and developmental neurocognitive literatures to characterize a variety of activities and cognitive processes that emerge in the presence of conspecifics. We provide here an overview of the current status of social attention as a construct, as reflected in its appearance in research studies, and we offer a framework for characterizing the extant literature based on the functions of social attention processes: as behavior for social communication, as motivation to engage in social communication, and as a form of basic visual attention in the context of other social agents. We then provide two overarching questions to guide future research efforts directed toward establishing the utility of social attention as an independent and/or unified construct. We then consider implications and recommendations for future research efforts.
Preschoolers' Mind‐related Comments During Collaborative Problem‐solving: Parental Contributions and Developmental Outcomes
Authors: Lundy Brenda L. , Fyfe Gracee
Published: December 2015

Preschool children's mind‐related comments were analyzed during collaborative problem‐solving interactions with mothers and fathers, and in relation to parental mind‐mindedness (MM) and children's concurrent theory of mind (ToM). Seventy‐two parents (36 fathers, 36 mothers) and their four‐year‐olds participated. Parents' comments to encourage independent thinking and children's own mind‐related comments were expected to mediate, in serial, the relationship between parental MM and children's ToM. The proposed model of mediation received empirical confirmation. In addition, mothers and fathers were found to perform similarly on two measures of MM and in their usage of autonomy promoting and control comments. Finally, no differences were found in the frequency of children's mind‐related comments during interactions with fathers and mothers.
Probabilistic soil mapping by Bayesian inference to assess suitability for derocking in northwest Syria
Authors: Hawinkel P. , De Pauw E. , Deckers J.
Published: December 2015

Land reclamation by rock removal has wide potential in areas with shallow or rocky soils. In northwest Syria, this practice is hindered in its implementation by a lack of physical soil suitability data, principally soil rockiness and soil depth to hard rock. These soil properties were surveyed in a limited study area, resulting in a hard‐boundary thematic soil map (64–94% accuracy per property). Bayesian inference is proposed as a low‐cost upscaling method that yields a set of pixel‐based probability maps, providing improved input for spatial decision support models. Whereas the achieved spatial upscaling (from 2510 to 19 100 ha) outweighed the decrease in overall accuracy (down to 26–57%), probability maps require dedicated validation and manipulation procedures. This research contributes to methods for the creation, validation and interpretation of probabilistic soil property maps for quantitative land evaluation. First, we evaluated three postprocessing and validation methods for probabilistic soil property maps, identifying the use of ‘prediction rates’ as the best approach in a spatial planning context. Next, we demonstrated how the maps can support decision‐making for land management activities by simulating the expected losses and gains from interventions, in a decision‐theoretic approach. Based on the simulations, the investments in large‐scale derocking projects in northwest Syria will pay off in terms of increased agricultural productivity in less than 10 years.
Interpopulation hybridization generates meiotically stable rDNA epigenetic variants in allotetraploid Tragopogon mirus
Authors: Matyášek Roman , Dobešová Eva , Húska Dalibor , Ježková Ivana , Soltis Pamela S. , Soltis Douglas E. , Kovařík Aleš
Published: December 2015

Uniparental silencing of 35S rRNA genes (rDNA), known as nucleolar dominance (ND), is common in interspecific hybrids. Allotetraploid Tragopogon mirus composed of Tragopogon dubius (d) and Tragopogon porrifolius (p) genomes shows highly variable ND. To examine the molecular basis of such variation, we studied the genetic and epigenetic features of rDNA homeologs in several lines derived from recently and independently formed natural populations. Inbred lines derived from T. mirus with a dominant d‐rDNA homeolog transmitted this expression pattern over generations, which may explain why it is prevalent among natural populations. In contrast, lines derived from the p‐rDNA dominant progenitor were meiotically unstable, frequently switching to co‐dominance. Interpopulation crosses between progenitors displaying reciprocal ND resulted in d‐rDNA dominance, indicating immediate suppression of p‐homeologs in F1 hybrids. Original p‐rDNA dominance was not restored in later generations, even in those segregants that inherited the corresponding parental rDNA genotype, thus indicating the generation of additional p‐rDNA and d‐rDNA epigenetic variants. Despite preserved intergenic spacer (IGS) structure, they showed altered cytosine methylation and chromatin condensation patterns, and a correlation between expression, hypomethylation of RNA Pol I promoters and chromatin decondensation was apparent. Reversion of such epigenetic variants occurred rarely, resulting in co‐dominance maintained in individuals with distinct genotypes. Generally, interpopulation crosses may generate epialleles that are not present in natural populations, underlying epigenetic dynamics in young allopolyploids. We hypothesize that highly expressed variants with distinct IGS features may induce heritable epigenetic reprogramming of the partner rDNA arrays, harmonizing the expression of thousands of genes in allopolyploids.
Shape matters: the effect of red blood cell shape on perfusion of an artificial microvascular network
Authors: Piety Nathaniel Z. , Reinhart Walter H. , Pourreau Patrick H. , Abidi Rajaa , Shevkoplyas Sergey S.
Published: December 2015

BACKGROUND

The shape of human red blood cells (RBCs) deteriorates progressively throughout hypothermic storage, with echinocytosis being the most prevalent pathway of this morphologic lesion. As a result, each unit of stored blood contains a heterogeneous mixture of cells in various stages of echinocytosis and normal discocytes. Here we studied how the change in shape of RBCs following along the path of the echinocytic transformation affects perfusion of an artificial microvascular network (AMVN).

STUDY DESIGN AND METHODS

Blood samples were obtained from healthy consenting volunteers. RBCs were leukoreduced, resuspended in saline, and treated with various concentrations of sodium salicylate to induce shape changes approximating the stages of echinocytosis experienced by RBCs during hypothermic storage (e.g., discocyte, echinocyte I, echinocyte II, echinocyte III, spheroechinocyte, and spherocyte). The AMVN perfusion rate was measured for 40% hematocrit suspensions of RBCs with different shapes.

RESULTS

The AMVN perfusion rates for RBCs with discocyte and echinocyte I shapes were similar, but there was a significant decline in the AMVN perfusion rate between RBCs with shapes approximating each subsequent stage of echinocytosis. The difference in AMVN perfusion between discocytes and spherocytes (the last stage of the echinocytic transformation) was 34%.

CONCLUSION

The change in shape of RBCs from normal discocytes progressively through various stages of echinocytosis to spherocytes produced a substantial decline in the ability of these cells to perfuse an AMVN. Echinocytosis induced by hypothermic storage could therefore be responsible for a similarly substantial impairment of deformability previously observed for stored RBCs.
New to the Board: A Case Study of Canadian Tire Corporation and the Potential Purchase of the Forzani Group Limited
Authors: Naraine Michael L. , Dixon Jess C. , Horton Candice
Published: December 2015

This case study explores the potential purchase of the Forzani Group Limited by the Canadian Tire Corporation. Students take on the role of Sara Brown, a new member of Canadian Tire’s board of directors. With an emergency meeting scheduled for the following morning to decide the fate of the proposed acquisition, Brown has been called upon to provide input to the board given her aptitude for corporate acquisitions and mergers. The case profiles both companies and details the state of the retail sport industry in Canada. Notably, there is emphasis on company product offerings (e.g., merchandise), financials (e.g., balance sheets), and goodwill (e.g., charities) to provide students with pertinent information to develop their argument(s) for and/or against the acquisition. Primary learning objectives include engaging in environmental scanning exercises (e.g., SWOT analyses) and evaluating market forces present in the retail sporting goods industry.
Cardiopulmonary Exercise Testing in Children and Adolescents with High Body Mass Index
Authors: Cooper Dan M. , Leu Szu-Yun , Taylor-Lucas Candice , Lu Kim , Galassetti Pietro , Radom-Aizik Shlomit
Published: December 2015

Consensus has yet to be achieved on whether obesity is inexorably tied to poor fitness. We tested the hypothesis that appropriate reference of cardiopulmonary exercise testing (CPET) variables to lean body mass (LBM) would eliminate differences in fitness between high-BMI (≥ 95th percentile, n = 72, 50% female) and normal-BMI (< 85th percentile, n = 142, 49% female), otherwise-healthy children and adolescents typically seen when referencing body weight. We measured body composition with dual x-ray absorptiometry (DXA) and CPET variables from cycle ergometry using both peak values and submaximal exercise slopes (peak VO2, ΔVO2/ΔHR, ΔWR/ΔHR, ΔVO2/ΔWR, and ΔVE/ΔVCO2). In contrast to our hypothesis, referencing to LBM tended to lessen, but did not eliminate, the differences (peak VO2 [p < .004] and ΔVO2/ΔHR [p < .02]) in males and females; ΔWR/ΔHR differed between the two groups in females (p = .041) but not males (p = .1). The mean percent predicted values for all CPET variables were below 100% in the high-BMI group. The pattern of CPET abnormalities suggested a pervasive impairment of O2 delivery in the high-BMI group (ΔVO2/ΔWR was in fact highest in normal-BMI males). Tailoring lifestyle interventions to the specific fitness capabilities of each child (personalized exercise medicine) may be one of the ways to stem what has been an intractable epidemic.
Antibiofilm Activity of Electrical Current in a Catheter Model
Authors: Voegele Paul , Badiola Jon , Schmidt-Malan Suzannah M. , Karau Melissa J. , Greenwood-Quaintance Kerryl E. , Mandrekar Jayawant N. , Patel Robin
Published: December 2015

Catheter-associated infections are difficult to treat with available antimicrobial agents because of their biofilm etiology. We examined the effect of low-amperage direct electrical current (DC) exposure on established bacterial and fungal biofilms in a novel experimental
in vitro
catheter model.
Staphylococcus epidermidis
,
Staphylococcus aureus
,
Escherichia coli
,
Pseudomonas aeruginosa
, and
Candida parapsilosis
biofilms were grown on the inside surfaces of polyvinyl chloride (PVC) catheters, after which 0, 100, 200, or 500 μA of DC was delivered via intraluminally placed platinum electrodes. Catheter biofilms and intraluminal fluid were quantitatively cultured after 24 h and 4 days of DC exposure. Time- and dose-dependent biofilm killing was observed with all amperages and durations of DC administration. Twenty-four hours of 500 μA of DC sterilized the intraluminal fluid for all bacterial species studied; no viable bacteria were detected after treatment of
S. epidermidis
and
S. aureus
biofilms with 500 μA of DC for 4 days.
Mutations That Enhance the Ciprofloxacin Resistance of Escherichia coli with
qnrA1
Authors: Vinué Laura , Corcoran Marian A. , Hooper David C. , Jacoby George A.
Published: December 2015

Plasmid-mediated
qnr
genes provide only a modest decrease in quinolone susceptibility but facilitate the selection of higher-level resistance. In
Escherichia coli
strain J53 without
qnr
, ciprofloxacin resistance often involves mutations in the GyrA subunit of DNA gyrase. Mutations in
gyrA
were absent, however, when 43 mutants with decreased ciprofloxacin susceptibility were selected from J53(pMG252) with
qnrA1
. Instead, in 13 mutants, individual and whole-genome sequencing identified mutations in
marR
and
soxR
associated with increased expression of
marA
and
soxS
and, through them, increased expression of the AcrAB pump, which effluxes quinolones. Nine mutants had increased expression of the MdtE efflux pump, and six demonstrated increased expression of the
ydhE
pump gene. Many efflux mutants also had increased resistance to novobiocin, another pump substrate, but other mutants were novobiocin hypersusceptible. Mutations in
rfaD
and
rfaE
in the pathway for inner core lipopolysaccharide (LPS) biosynthesis were identified in five such strains. Many of the pump and LPS mutants had decreased expression of OmpF, the major porin channel for ciprofloxacin entry. Three mutants had increased expression of
qnrA
that persisted when pMG252 from these strains was outcrossed.
gyrA
mutations were also rare when mutants with decreased ciprofloxacin susceptibility were selected from
E. coli
J53 with
aac(6
′
)-Ib-cr
or
qepA
. We suggest that multiple genes conferring low-level resistance contribute to enhanced ciprofloxacin resistance selected from an
E. coli
strain carrying
qnrA1
,
aac(6
′
)-Ib-cr
, or
qepA
because these determinants decrease the effective ciprofloxacin concentration and allow more common but lower-resistance mutations than those in
gyrA
to predominate.
Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs
Authors: Fernandes Chantal , Prados-Rosales Rafael , Silva Branca M. A. , Nakouzi-Naranjo Antonio , Zuzarte Mónica , Chatterjee Subhasish , Stark Ruth E. , Casadevall Arturo , Gonçalves Teresa
Published: December 2015

The importance of
Alternaria
species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on
Alternaria infectoria
, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by
A. infectoria
, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that
A. infectoria
increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that
A. infectoria
activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized
A. infectoria
cell walls. In summary,
A. infectoria
synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis.
Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 2
Authors: Drusano G. L. , Hope William , MacGowan Alasdair , Louie Arnold
Published: December 2015

We are in a crisis of bacterial resistance. For economic reasons, most pharmaceutical companies are abandoning antimicrobial discovery efforts, while, in health care itself, infection control and antibiotic stewardship programs have generally failed to prevent the spread of drug-resistant bacteria. At this point, what can be done? The first step has been taken. Governments and international bodies have declared there is a worldwide crisis in antibiotic drug resistance. As discovery efforts begin anew, what more can be done to protect newly developing agents and improve the use of new drugs to suppress resistance emergence? A neglected path has been the use of recent knowledge regarding antibiotic dosing as single agents and in combination to minimize resistance emergence, while also providing sufficient early bacterial kill. In this review, we look at the data for resistance suppression. Approaches include increasing the intensity of therapy to suppress resistant subpopulations; developing concepts of clinical breakpoints to include issues surrounding suppression of resistance; and paying attention to the duration of therapy, which is another important issue for resistance suppression. New understanding of optimizing combination therapy is of interest for difficult-to-treat pathogens like
Pseudomonas aeruginosa
,
Acinetobacter
spp., and multidrug-resistant (MDR)
Enterobacteriaceae
. These lessons need to be applied to our old drugs as well to preserve them and to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chemical entities should have a resistance suppression plan at the time of regulatory review. In this way, we can make the best of our current situation and improve future prospects.