bluuebunny/crossref_metadata_2025 huggingface dataset:
Over‐expression of the molecular chaperone Hsp104 in Saccharomyces cerevisiae results in the malpartition of [PSI+] propagons
Authors: Ness Frederique , Cox Brian S. , Wongwigkarn Jintana , Naeimi Wesley R. , Tuite Mick F.
Published: January 2017

The ability of a yeast cell to propagate [PSI+], the prion form of the Sup35 protein, is dependent on the molecular chaperone Hsp104. Inhibition of Hsp104 function in yeast cells leads to a failure to generate new propagons, the molecular entities necessary for [PSI+] propagation in dividing cells and they get diluted out as cells multiply. Over‐expression of Hsp104 also leads to [PSI+] prion loss and this has been assumed to arise from the complete disaggregation of the Sup35 prion polymers. However, in conditions of Hsp104 over‐expression in [PSI+] cells we find no release of monomers from Sup35 polymers, no monomerization of aggregated Sup35 which is not accounted for by the proportion of prion‐free [psi‐] cells present, no change in the molecular weight of Sup35‐containing SDS‐resistant polymers and no significant decrease in average propagon numbers in the population as a whole. Furthermore, they show that over‐expression of Hsp104 does not interfere with the incorporation of newly synthesised Sup35 into polymers, nor with the multiplication of propagons following their depletion in numbers while growing in the presence of guanidine hydrochloride. Rather, they present evidence that over‐expression of Hsp104 causes malpartition of [PSI+] propagons between mother and daughter cells in a sub‐population of cells during cell division thereby generating prion‐free [psi−] cells.
Resistance diagnosis and the changing economics of antibiotic discovery
Authors: McAdams David
Published: January 2017

Point‐of‐care diagnostics that can determine an infection's antibiotic sensitivity increase the profitability of new antibiotics that enjoy patent protection, even when such diagnostics reduce the quantity of antibiotics sold. Advances in the science and technology underpinning rapid resistance diagnostics can therefore be expected to spur efforts to discover and develop new antibiotics, especially those with a narrow spectrum of activity that would otherwise fail to find a market.
Married Black men's observations of fathers' teachings about husbandhood
Authors: HURT TERA R. , SHEARS JEFFREY K. , O'CONNOR MARGARET C. , HODGE SHARON B.
Published: January 2017

It is important to investigate the ways in which sons learn about marriage from men, including biological fathers, male relatives, and social fathers. This study's purpose is to explore Black sons' observations of fathers' teachings about husbandhood. Semistructured interviews were conducted with 52 married Black men who participated in the Pathways to Marriage project in 2010. Findings highlighted developmental pathways and family processes related to modeling husbandhood, demonstrating trust and commitment, managing conflict, protecting and providing, displaying teamwork and partnership, showing love and affection, and imparting beliefs and values. Implications and recommendations for future studies are also discussed.
Modeling Strategic Behavior in The Competitive Newsvendor Problem: An Experimental Investigation
Authors: Feng Tianjun , Zhang Yinghao
Published: January 2017

This study experimentally investigates ordering behavior in the competitive newsvendor problem. We consider a duopoly market setting with two identical newsvendors selling the same perishable goods in a common market. Our experimental results show that average observed orders systematically deviate from the Nash equilibrium, and exhibit a similar pull‐to‐center pattern as in the classic non‐competitive newsvendor experiments: average orders fall below the Nash equilibrium in the high‐margin condition, and above the Nash equilibrium in the low‐margin condition. More importantly, the observed orders in the duopoly market are significantly higher than that in the non‐competitive newsvendor market, even in situations where standard inventory models predict no difference. We explain the ordering behavior using a strategic experience‐weighted attraction (EWA) model, which captures players' propensities for strategic thinking in game settings. Our empirical analysis suggests that the strategic EWA model generates more accurate predictions of future ordering behavior than an existing linear adaptive model without concerning strategic thinking. Further analysis shows that individuals are heterogeneous in their propensities to be a strategic player. Our research indicates the importance of modeling strategic behavior when analyzing behavioral decisions in competitive (game) environments.
Patterns of infections, aetiological agents and antimicrobial resistance at a tertiary care hospital in northern Tanzania
Authors: Kumburu Happiness Houka , Sonda Tolbert , Mmbaga Blandina Theophil , Alifrangis Michael , Lund Ole , Kibiki Gibson , Aarestrup Frank M.
Published: January 2017

Objective

To determine the causative agents of infections and their antimicrobial susceptibility at a tertiary care hospital in Moshi, Tanzania, to guide optimal treatment.

Methods

A total of 590 specimens (stool (56), sputum (122), blood (126) and wound swabs (286)) were collected from 575 patients admitted in the medical and surgical departments. The bacterial species were determined by conventional methods, and disc diffusion was used to determine the antimicrobial susceptibility pattern of the bacterial isolates.

Results

A total of 249 (42.2%) specimens were culture‐positive yielding a total of 377 isolates. A wide range of bacteria was isolated, the most predominant being Gram‐negative bacteria: Proteus spp. (n = 48, 12.7%), Escherichia coli (n = 44, 11.7%), Pseudomonas spp. (n = 40, 10.6%) and Klebsiella spp (n = 38, 10.1%). Wound infections were characterised by multiple isolates (n = 293, 77.7%), with the most frequent being Proteus spp. (n = 44, 15%), Pseudomonas (n = 37, 12.6%), Staphylococcus (n = 29, 9.9%) and Klebsiella spp. (n = 28, 9.6%). All Staphylococcus aureus tested were resistant to penicillin (n = 22, 100%) and susceptible to vancomycin. Significant resistance to cephalosporins such as cefazolin (n = 62, 72.9%), ceftriaxone (n = 44, 51.8%) and ceftazidime (n = 40, 37.4%) was observed in Gram‐negative bacteria, as well as resistance to cefoxitin (n = 6, 27.3%) in S. aureus.

Conclusion

The study has revealed a wide range of causative agents, with an alarming rate of resistance to the commonly used antimicrobial agents. Furthermore, the bacterial spectrum differs from those often observed in high‐income countries. This highlights the imperative of regular generation of data on aetiological agents and their antimicrobial susceptibility patterns especially in infectious disease endemic settings. The key steps would be to ensure the diagnostic capacity at a sufficient number of sites and implement structures to routinely exchange, compare, analyse and report data. Sentinel sites (hospitals) across the country (and region) should report on a representative subset of bacterial species and their susceptibility to drugs at least annually. A central organising body should collate the data and report to relevant national and international stakeholders.
Ultrasound‐guided intracardiac xenotransfusion of canine packed red blood cells and epinephrine to the left ventricle of a severely anemic cat during cardiopulmonary resuscitation
Authors: Oron Liron , Bruchim Yaron , Klainbart Sigal , Kelmer Efrat
Published: January 2017

Objective

To describe the use of an ultrasound‐guided intracardiac xenotransfusion of canine packed red blood cells (pRBC) to the left ventricle of a severely anemic cat during cardiopulmonary resuscitation (CPR).

Case Summary

An 8‐year‐old previously healthy neutered female cat was presented with severe weakness after she had disappeared for 1 month. On presentation, the cat was in hypovolemic shock, laterally recumbent, and severely anemic with massive flea infestation. Within minutes of admission, the cat became agonal and suffered cardiopulmonary arrest. CPR was immediately initiated; however, attempts to gain IV access during CPR were unsuccessful. As the cat's blood type was yet unknown, 10 mL of canine pRBC was transfused directly into the left ventricular chamber using ultrasound guidance, as well as 0.02 mg/kg of epinephrine using a similar technique. The cat regained cardiac activity and once the jugular vein was cannulated it received 20 additional mL of canine pRBC intravenously. The packed cell volume and total plasma protein following the intracardiac transfusion were 0.09 L/L [9%] and 30 g/L [3.0 g/dL], respectively. Subsequent blood typing revealed the cat had type B blood. The cat was discharged 3 days post‐CPR and was alive and doing well 3 months following discharge.

New or Unique Information Provided

This is the first reported case of ultrasound‐guided intracardiac canine‐to‐feline xenotransfusion during CPR.
The consequences of avian ocular trauma: histopathological evidence and implications of acute and chronic disease
Authors: Moore Bret A. , Teixeira Leandro B. C. , Sponsel William E. , Dubielzig Richard R.
Published: January 2017

Objective

To present a description and categorization of the histopathological lesions in avian ocular trauma.

Animal studied

Seventy‐five birds diagnosed with ocular trauma at to the Comparative Ocular Pathology Laboratory of Wisconsin.

Procedures

Histological slides were reviewed, and the type of trauma was classified by cause into either (i) blunt trauma or (ii) penetrating trauma and by duration into (i) acute or (ii) chronic.

Results

Blunt trauma was the most common source of trauma, and the most frequent lesions were observed in the retina (91%), with 71% of retinas having a tear or detachment and 46% of retinas showing chronic degenerative changes. Damage to the iris/ciliary body was present in 77% of cases. Corneal (17%) and lens (31%) lesions were relatively low. Acute traumatic events had a higher prevalence of readily identifiable discrete retinal tears/detachments (64%). Nearly all cases of chronic trauma exhibited chronic retinal lesions (93.7%), as well as a greater percentage of cartilage/bone lesions (71.4%), irido/cyclodialysis (51.9%), lenticular lesions (72.7%), and corneal damage (83.3%). However, the incidence of iridocyclodialysis was roughly equivalent for acute and chronic blunt trauma.

Conclusions

Ocular trauma can lead to profound acute and chronic lesions within the eye. Here, we provide insight into understanding ocular damage caused by trauma, which may help future studies suggest new therapeutic options and provide insight regarding the releasability of avian wildlife.
Clinical utility of the basophil activation test for analysis of allergic transfusion reactions: a pilot study
Authors: Okamura I. , Matsuyama N. , Yasui K. , Hirayama F. , Ikeda T.
Published: January 2017

Background and Objectives

In previous studies, we demonstrated that the basophil‐activating effects of supernatants found in residual‐transfused platelet concentrates (PC‐SNs) on whole blood basophils in cases of allergic transfusion reactions (ATRs) could be assessed by the basophil activation test (BAT) in terms of allergen/IgE dependency. However, in these studies, the basophils were derived from third‐party healthy volunteers. In this study, we performed BAT using patients' own blood basophils to analyse ATRs.

Materials and Methods

The BAT was performed in two cases of severe ATRs using residual PC‐SNs and the patients' own basophils in the presence and absence of dasatinib, an inhibitor of IgE‐mediated basophil activation.

Results

In both cases, PC‐SNs exhibited basophil‐activating activity against the patients' basophils, but not against basophils from third‐party healthy volunteers. In addition, basophil activation was inhibited in the presence of dasatinib, indicating that the basophils were activated in an allergen/IgE‐dependent manner. Of note, the basophils in Case 2, but not in Case 1, were activated by PC‐SNs from some unrelated non‐haemolytic transfusion reaction cases.

Conclusion

This pilot study indicates that the BAT may be useful in clarifying the causal relationship between ATRs and transfused blood as well as in elucidating the mechanisms behind ATRs considering the allergen/IgE‐dependent pathway.
Reviewer Acknowledgements
Authors: Willianms Ellery
Published: January 2017

Business and Management Studies (BMS) would like to acknowledge the following reviewers for their assistance with peer review of manuscripts for this issue. Many authors, regardless of whether BMS publishes their work, appreciate the helpful feedback provided by the reviewers. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Each of the reviewers listed below returned at least one review for this issue. Reviewers for Volume 2, Number 1 Abdul-Kahar Adam Arash Riasi Athina Qendro Christer Thörnqvist Florin Peci Gabriela Antošová Hung-Che Wu Kenichi Shimizu Mohammad Soliman Mythili Kolluru Oleksandr Mosin Olha Komelina Olumide Olasimbo Jaiyeoba Ombretta Caldarice Rashedul Hasan Seyed Mehrdad Miraftab Zadeh Sourabh Sharma Tetiana Paientko Yu-Shou Su Zoran Mastilo   Ellery Willianms Editorial Assistant On behalf of, The Editorial Board of Business and Management Studies Redfame Publishing 9450 SW Gemini Dr. #99416 Beaverton, OR 97008, USA URL: http://bms.redfame.com
Reviewer Acknowledgements
Authors: Young James
Published: January 2017

International Journal of Social Science Studies (IJSSS) would like to thank the following reviewers for reviewing manuscripts from October 9, 2012, to April 1, 2013. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Many authors, regardless of whether IJSSS publishes their work, appreciate the helpful feedback provided by the reviewers. Redfame Publishing appreciates the following reviewers’ rigorous and conscientious efforts for this journal. Each of the reviewers listed below returned at least one review during this period.   Patricia Wiener Anna Maria Mouza Sigit D. Arifwidodo Daniele Schilirò Mariano D. Perelman Troy Lovata Mónica Martínez Gómez Remigiusz Janusz Kijak Matthew Dabros Joan Garcia Garriga Kim L. Stansbury Robert Costello Joy D. Patton Sudershan Pasupuleti Ludmila Ribeiro Gabriela Kütting Daniel Topinka Marilynne Kirshbaum Regina Kuersten-Hogan Meagan Parmley George E. Higgins
Reviewer Acknowledgements
Authors: Young James
Published: January 2017

International Journal of Social Science Studies (IJSSS) would like to thank the following reviewers for reviewing manuscripts from April 2, 2013, to September 15, 2013. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Many authors, regardless of whether IJSSS publishes their work, appreciate the helpful feedback provided by the reviewers. Redfame Publishing appreciates the following reviewers’ rigorous and conscientious efforts for this journal. Each of the reviewers listed below returned at least one review during this period.Anna Maria Mouza Patricia Wiener Mariano D. Perelman Jamie Spinney Jose A. Amozurrutia Paulito Valeriano Hilario Ludmila Ribeiro Sudershan Pasupuleti Mónica Martínez Gómez Remigiusz Janusz Kijak Matthew Dabros Mohammed Nasarat Zitha Mokomane Mei-Se Chien Parveen Kaur Shani Bardach Deirdre M. Warren Lee Pugalis Shahadat Hossain Caroline Mellgren Linda Chernus Joy D. Patton Daniele Schilirò Robert Costello Torry Dickinson Dennis Erasga Matti Viren Beining Zhang Dejian Wang
Reviewer Acknowledgements
Authors: Smith Robert
Published: January 2017

Journal of Education and Training Studies (JETS) would like to thank the following reviewers for reviewing manuscripts from April 1, 2014, to September 30, 2014. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Many authors, regardless of whether JETS publishes their work, appreciate the helpful feedback provided by the reviewers. Redfame Publishing appreciates the following reviewers’ rigorous and conscientious efforts for this journal. Each of the reviewers listed below returned at least one review during this period. Ahmet KARA Ardi Marwan Barbara Hill Betsy L. Diegel Charlotte Alverson Chris Prince Udochukwu Njoku Clara Vasconcelos Dalya Abdulla Fátima Pereira Greg Rickwood Hassan Shaaban Ian Menter Intakhab A. Khan Jacqueline Onchwari Jayaluxmi Naidoo Jeyavel Sundaramoorthy Julie Ernst Kelly Amanda Train Leann M Stadtlander Marieke van der Schaaf Michael Baron Nemer Frayha Richard Beresford Richard Penny Ryan Daniel Semiyu Adejare Aderibigbe Ugo Pace
Reviewer Acknowledgements
Authors: Smith Robert
Published: January 2017

Journal of Education and Training Studies (JETS) would like to acknowledge the following reviewers for their assistance with peer review of manuscripts for this issue. Many authors, regardless of whether JETS publishes their work, appreciate the helpful feedback provided by the reviewers. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Each of the reviewers listed below returned at least one review for this issue. Reviewers for Volume 4, Number 8 Brenda L. Shook Cynthia M. Compton David A. Compton Davy Seligin Elena Jerves Erickzon Astorga Fatma Ozudogru Katya De Giovanni Laima Kyburiene Puneet S. Gill Richard Penny Suzan Kavanoz                 Robert Smith Editorial Assistant On behalf of, The Editorial Board of Journal of Education and Training Studies Redfame Publishing 9450 SW Gemini Dr. #99416 Beaverton, OR 97008, USA URL: http://jets.redfame.com
Reviewer Acknowledgements
Authors: Smith Robert
Published: January 2017

Journal of Education and Training Studies (JETS) would like to acknowledge the following reviewers for their assistance with peer review of manuscripts for this issue. Many authors, regardless of whether JETS publishes their work, appreciate the helpful feedback provided by the reviewers. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Each of the reviewers listed below returned at least one review for this issue. Reviewers for Volume 4, Number 9   Abdelkader Hermas António Calha Betsy Diegel Cynthia M. Compton Dodzi Amemado Donna Smith Ebrahim Mohammadpour Elena Jerves Erickzon Astorga Fatma Ozudogru Intakhab Khan Jeyavel Sundaramoorthy Jiao Ji John Cowan Katya De Giovanni Kevin Tarlow Laima Kyburiene Lorna Enerva Mehmet Inan Min Gui Mu-hsuan Chou Niveen M. Zayed Puneet S. Gill Richard H. Martin Samad Mirza Suzani Sharma Sashi Suzan Kavanoz               Robert Smith Editorial Assistant On behalf of, The Editorial Board of Journal of Education and Training Studies Redfame Publishing 9450 SW Gemini Dr. #99416 Beaverton, OR 97008, USA URL: http://jets.redfame.com
Modulation of the work function of graphene by Na and Cl coadsorbed on opposite sides on graphene
Authors: Yuan Guang , Song Xinxiang , Mimura Hidenori
Published: January 2017

The influence of Na and Cl atoms coadsorption on the work functions (WFs) of graphene was investigated by first-principles calculations under density functional theory. Although there is very little net charge on the surface of graphene due to charge redistribution among the adsorbates and substrate, the WFs of graphene still change dramatically.
Papers of note in
Nature
541
(7635)
Authors: Foley John F.
Published: January 2017

This week’s articles show how targeting a fatty acid receptor blocks metastasis, reveal the structural basis for the mechanism of action of a potassium channel, and indicate that splicing factor 1 is required for life span extension in worms.
Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells
Authors: Koniordou Markela , Patterson Stephen , Wyllie Susan , Seifert Karin
Published: January 2017

This study characterized the
in vitro
potencies of antileishmanial agents against intracellular
Leishmania donovani
amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells, and mouse peritoneal exudate macrophages (PEMs). Host cell-dependent potency was confirmed for pentavalent and trivalent antimony. Fexinidazole was inactive against intracellular amastigotes across the host cell panel. Fexinidazole sulfone, (
R
)-PA-824, (
S
)-PA-824, and VL-2098 displayed similar potency in all of the host cells tested.
SCY-078 Is Fungicidal against Candida Species in Time-Kill Studies
Authors: Scorneaux Bernard , Angulo David , Borroto-Esoda Katyna , Ghannoum Mahmoud , Peel Michael , Wring Stephen
Published: January 2017

SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis.
In vitro
susceptibilities by broth microdilution, antifungal carryover, and time-kill dynamics were determined for three reference (ATCC) strains (
Candida albicans
90028,
Candida parapsilosis
90018, and
Candida tropicalis
750), a quality-control (QC) strain (
Candida krusei
6258), and four other strains (
C. albicans
MYA-2732, 64124, and 76485 and
Candida glabrata
90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators. For time-kill experiments, SCY-078 and CASP were evaluated at 0.25, 1, 2, 4, 8, and 16 times the MIC
80
, and FLU and VRC were evaluated at 4× MIC
80
. The time to reach 50%, 90%, and 99.9% reduction in the number of CFUs from the starting inoculum was determined. Net change in the number of CFU per milliliter was used to determine 50% and 90% effective concentrations and maximum effect (EC
50
, EC
90
, and
E
max
, respectively). The SCY-078 MIC range was between 0.0625 and 1 μg/ml and generally similar to that of CASP. Antifungal carryover was not observed for SCY-078. SCY-078 was fungicidal against seven isolates at ≥4× MIC (kill of ≥3 log
10
) and achieved a 1.7-log
10
reduction in CFU count/milliliter against
C. albicans
90028. CASP behaved similarly against each isolate and achieved a 1.5-log
10
reduction in the number of CFU/milliliter against
C. albicans
90028. Reductions of 50% in CFU count/milliliter were achieved rapidly (1 to 2.8 h); fungicidal endpoints were reached at 12.1 to 21.8 h at ≥4× MIC. EC
90
was reached at ∼5× MIC at each time point to 24 h. The EC
50
and EC
90
values were generally similar (8 to 24 h). Time-kill behavior of CASP was similar to that of SCY-078. FLC and VRC were fungistatic. Overall, SCY-078 has primarily fungicidal activity against
Candida
spp. and behaved comparably to CASP.
In Vitro
Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae
Authors: Farrell D. J. , Sader H. S. , Rhomberg P. R. , Scangarella-Oman N. E. , Flamm R. K.
Published: January 2017

Gepotidacin (formerly GSK2140944) is a novel, first-in-class, triazaacenaphthylene antibacterial that inhibits bacterial DNA gyrase and topoisomerase IV via a unique mechanism and has demonstrated
in vitro
activity against
Neisseria gonorrhoeae
, including drug-resistant strains, and also targets pathogens associated with other conventional and biothreat infections. Broth microdilution was used to evaluate the MIC and minimum bactericidal concentration (MBC) activity of gepotidacin and comparators against 25
N. gonorrhoeae
strains (including five ciprofloxacin-nonsusceptible strains). Gepotidacin activity was also evaluated against three
N. gonorrhoeae
strains (including a ciprofloxacin-nonsusceptible strain) for resistance development, against three
N. gonorrhoeae
strains (including two tetracycline- and azithromycin-nonsusceptible strains) using time-kill kinetics and checkerboard methods, and against two
N. gonorrhoeae
strains for the investigation of postantibiotic (PAE) and subinhibitory (PAE-SME) effects. The MIC
50
and MIC
90
for gepotidacin against the 25
N. gonorrhoeae
isolates tested were 0.12 and 0.25 μg/ml, respectively. The MBC
50
and MBC
90
for gepotidacin were 0.25 and 0.5 μg/ml, respectively. Gepotidacin was bactericidal, and single-step resistance selection studies did not recover any mutants, indicating a low rate of spontaneous single-step resistance. For combinations of gepotidacin and comparators tested using checkerboard methods, there were no instances where antagonism occurred and only one instance of synergy (with moxifloxacin; fractional inhibitory concentration, 0.375). This was not confirmed by
in vitro
time-kill studies. The PAE for gepotidacin against the wild-type strain ranged from 0.5 to >2.5 h, and the PAE-SME was >2.5 h. These
in vitro
data indicate that further study of gepotidacin is warranted for potential use in treating infections caused by
N. gonorrhoeae
.
Molecular Epidemiology of Plasmodium falciparum kelch13 Mutations in Senegal Determined by Using Targeted Amplicon Deep Sequencing
Authors: Talundzic Eldin , Ndiaye Yaye D. , Deme Awa B. , Olsen Christian , Patel Dhruviben S. , Biliya Shweta , Daniels Rachel , Vannberg Fredrik O. , Volkman Sarah K. , Udhayakumar Venkatachalam , Ndiaye Daouda
Published: January 2017

The emergence of
Plasmodium falciparum
resistance to artemisinin in Southeast Asia threatens malaria control and elimination activities worldwide. Multiple polymorphisms in the
P. falciparum kelch
gene found in chromosome 13 (
Pfk13
) have been associated with artemisinin resistance. Surveillance of potential drug resistance loci within a population that may emerge under increasing drug pressure is an important public health activity. In this context,
P. falciparum
infections from an observational surveillance study in Senegal were genotyped using targeted amplicon deep sequencing (TADS) for
Pfk13
polymorphisms. The results were compared to previously reported
Pfk13
polymorphisms from around the world. A total of 22
Pfk13
propeller domain polymorphisms were identified in this study, of which 12 have previously not been reported. Interestingly, of the 10 polymorphisms identified in the present study that were also previously reported, all had a different amino acid substitution at these codon positions. Most of the polymorphisms were present at low frequencies and were confined to single isolates, suggesting they are likely transient polymorphisms that are part of naturally evolving parasite populations. The results of this study underscore the need to identify potential drug resistance loci existing within a population, which may emerge under increasing drug pressure.
Ribosomal Mutations Conferring Macrolide Resistance in Legionella pneumophila
Authors: Descours Ghislaine , Ginevra Christophe , Jacotin Nathalie , Forey Françoise , Chastang Joëlle , Kay Elisabeth , Etienne Jerome , Lina Gérard , Doublet Patricia , Jarraud Sophie
Published: January 2017

Monitoring the emergence of antibiotic resistance is a recent issue in the treatment of Legionnaires' disease. Macrolides are recommended as first-line therapy, but resistance mechanisms have not been studied inLegionellaspecies. Our aim was to determine the molecular basis of macrolide resistance inL. pneumophila. Twelve independent lineages from a common susceptibleL. pneumophilaancestral strain were propagated under conditions of erythromycin or azithromycin pressure to produce high-level macrolide resistance. Whole-genome sequencing was performed on 12 selected clones, and we investigated mutations common to all lineages. We reconstructed the dynamics of mutation for each lineage and demonstrated their involvement in decreased susceptibility to macrolides. The resistant mutants were produced in a limited number of passages to obtain a 4,096-fold increase in erythromycin MICs. Mutations affected highly conserved 5-amino-acid regions of L4 and L22 ribosomal proteins and of domain V of 23S rRNA (G2057, A2058, A2059, and C2611 nucleotides). The early mechanisms mainly affected L4 and L22 proteins and induced a 32-fold increase in the MICs of the selector drug. Additional mutations related to 23S rRNA mostly occurred later and were responsible for a major increase of macrolide MICs, depending on the mutated nucleotide, the substitution, and the number of mutated genes among the threerrlcopies. The major mechanisms of the decreased susceptibility to macrolides inL. pneumophilaand their dynamics were determined. The results showed that macrolide resistance could be easily selected inL. pneumophilaand warrant further investigations in both clinical and environmental settings.
Mutation in an Unannotated Protein Confers Carbapenem Resistance in Mycobacterium tuberculosis
Authors: Kumar Pankaj , Kaushik Amit , Bell Drew T. , Chauhan Varsha , Xia Fangfang , Stevens Rick L. , Lamichhane Gyanu
Published: January 2017

β-Lactams are the most widely used antibacterials. Among β-lactams, carbapenems are considered the last line of defense against recalcitrant infections. As recent developments have prompted consideration of carbapenems for treatment of drug-resistant tuberculosis, it is only a matter of time before
Mycobacterium tuberculosis
strains resistant to these drugs will emerge. In the present study, we investigated the genetic basis that confers such resistance. To our surprise, instead of mutations in the known β-lactam targets, a single nucleotide polymorphism in the
Rv2421c-Rv2422
intergenic region was common among
M. tuberculosis
mutants selected with meropenem or biapenem. We present data supporting the hypothesis that this locus harbors a previously unidentified gene that encodes a protein. This protein binds to β-lactams, slowly hydrolyzes the chromogenic β-lactam nitrocefin, and is inhibited by select penicillins and carbapenems and the β-lactamase inhibitor clavulanate. The mutation results in a W62R substitution that reduces the protein's nitrocefin-hydrolyzing activity and binding affinities for carbapenems.
Inhibition by Avibactam and Clavulanate of the β-Lactamases KPC-2 and CTX-M-15 Harboring the Substitution N
132
G in the Conserved SDN Motif
Authors: Ourghanlian Clément , Soroka Daria , Arthur Michel
Published: January 2017

The substitution N
132
G in the SDN motif of class A β-lactamases from rapidly growing mycobacteria was previously shown to impair their inhibition by avibactam but to improve the stability of acyl-enzymes formed with clavulanate. The same substitution was introduced in KPC-2 and CTX-M-15 to assess its impact on β-lactamases from
Enterobacteriaceae
and evaluate whether it may lead to resistance to the ceftazidime-avibactam combination. Kinetic parameters for the inhibition of the β-lactamases by avibactam and clavulanate were determined by spectrophotometry using nitrocefin as the substrate. The substitution N
132
G impaired (>1,000-fold) the efficacy of carbamylation of KPC-2 and CTX-M-15 by avibactam. The substitution improved the inhibition of KPC-2 by clavulanate due to reduced deacylation, whereas the presence or absence of N
132
G resulted in the inhibition of CTX-M-15 by clavulanate. The hydrolysis of amoxicillin and nitrocefin by KPC-2 and CTX-M-15 was moderately affected by the substitution N
132
G, but that of ceftazidime, ceftaroline, and aztreonam was drastically reduced. Isogenic strains producing KPC-2 and CTX-M-15 were constructed to assess the impact of the substitution N
132
G on the antibacterial activities of β-lactam–inhibitor combinations. For amoxicillin, the substitution resulted in resistance and susceptibility for avibactam and clavulanate, respectively. For ceftazidime, ceftaroline, and aztreonam, the negative impact of the substitution on β-lactamase activity prevented resistance to the β-lactam–avibactam combinations. In conclusion, the N
132
G substitution has profound effects on the substrate and inhibition profiles of class A β-lactamases, which are largely conserved in distantly related enzymes. Fortunately, the substitution does not lead to resistance to the ceftazidime-avibactam combination.
SseK1 and SseK3 Type III Secretion System Effectors Inhibit NF-κB Signaling and Necroptotic Cell Death in Salmonella-Infected Macrophages
Authors: Günster Regina A. , Matthews Sophie A. , Holden David W. , Thurston Teresa L. M.
Published: January 2017

Within host cells such as macrophages,
Salmonella enterica
translocates virulence (effector) proteins across its vacuolar membrane via the SPI-2 type III secretion system. Previously, it was shown that when expressed ectopically, the effectors SseK1 and SseK3 inhibit tumor necrosis factor alpha (TNF-α)-induced NF-κB activation. In this study, we show that ectopically expressed SseK1, SseK2, and SseK3 suppress TNF-α-induced, but not Toll-like receptor 4- or interleukin-induced, NF-κB activation. Inhibition required a DXD motif in SseK1 and SseK3, which is essential for the transfer of
N
-acetylglucosamine to arginine residues (arginine-GlcNAcylation). During macrophage infection, SseK1 and SseK3 inhibited NF-κB activity in an additive manner. SseK3-mediated inhibition of NF-κB activation did not require the only known host-binding partner of this effector, the E3-ubiquitin ligase TRIM32. SseK proteins also inhibited TNF-α-induced cell death during macrophage infection. Despite SseK1 and SseK3 inhibiting TNF-α-induced apoptosis upon ectopic expression in HeLa cells, the percentage of infected macrophages undergoing apoptosis was SseK independent. Instead, SseK proteins inhibited necroptotic cell death during macrophage infection. SseK1 and SseK3 caused GlcNAcylation of different proteins in infected macrophages, suggesting that these effectors have distinct substrate specificities. Indeed, SseK1 caused the GlcNAcylation of the death domain-containing proteins FADD and TRADD, whereas SseK3 expression resulted in weak GlcNAcylation of TRADD but not FADD. Additional, as-yet-unidentified substrates are likely to explain the additive phenotype of a
Salmonella
strain lacking both SseK1 and SseK3.
Identification of a Residue (Glu60) in TRAP Required for Inducing Efficient Transcription Termination at the
trp
Attenuator Independent of Binding Tryptophan and RNA
Authors: McAdams Natalie M. , Patterson Andrea , Gollnick Paul
Published: January 2017

Transcription of the tryptophan (
trp
) operon in
Bacillus subtilis
is regulated by an attenuation mechanism. Attenuation is controlled by the

t

rp
R
NA-binding
a
ttenuation
p
rotein (TRAP). TRAP binds to a site in the 5′ leader region of the nascent
trp
transcript in response to the presence of excess intracellular tryptophan. This binding induces transcription termination upstream of the structural genes of the operon. In prior attenuation models, the role of TRAP was only to alter the secondary structure of the leader region RNA so as to promote formation of the
trp
attenuator, which was presumed to function as an intrinsic terminator. However, formation of the attenuator alone has been shown to be insufficient to induce efficient termination, indicating that TRAP plays an additional role in this process. To further examine the function of TRAP, we performed a genetic selection for mutant TRAPs that bind tryptophan and RNA but show diminished termination at the
trp
attenuator. Five such TRAP mutants were obtained. Four of these have substitutions at Glu60, three of which are Lys (E60K) substitutions and the fourth of which is a Val (E60V) substitution. The fifth mutant obtained contains a substitution at Ile63, which is on the same β-strand of TRAP as Glu60. Purified E60K TRAP binds tryptophan and RNA with properties similar to those of the wild type but is defective at inducing termination at the
trp
attenuator
in vitro
.

IMPORTANCE
Prior models for attenuation control of the
B. subtilis trp
operon suggested that the only role for TRAP is to bind to the leader region RNA and alter its folding to induce formation of an intrinsic terminator. However, several recent studies suggested that TRAP plays an additional role in the termination mechanism. We hypothesized that this function could involve residues in TRAP other than those required to bind tryptophan and RNA. Here we obtained TRAP mutants with alterations at Glu60 that are deficient at inducing termination in the leader region while maintaining tryptophan and RNA binding properties similar to those of the WT protein. These studies provide additional evidence that TRAP-mediated transcription termination at the
trp
attenuator is neither intrinsic nor Rho dependent.
Quantifying the rise of the Himalaya orogen and implications for the South Asian monsoon
Authors: Ding Lin , Spicer R.A. , Yang Jian , Xu Qiang , Cai Fulong , Li Shun , Lai Qingzhou , Wang Houqi , Spicer T.E.V. , Yue Yahui , Shukla A. , Srivastava G. , Khan M. Ali , Bera S. , Mehrotra R.
Published: January 2017

We reconstruct the rise of a segment of the southern flank of the Himalaya-Tibet orogen, to the south of the Lhasa terrane, using a paleoaltimeter based on paleoenthalpy encoded in fossil leaves from two new assemblages in southern Tibet (Liuqu and Qiabulin) and four previously known floras from the Himalaya foreland basin. U-Pb dating of zircons constrains the Liuqu flora to the latest Paleocene (ca. 56 Ma) and the Qiabulin flora to the earliest Miocene (21–19 Ma). The proto-Himalaya grew slowly against a high (∼4 km) proto–Tibetan Plateau from ∼1 km in the late Paleocene to ∼2.3 km at the beginning of the Miocene, and achieved at least ∼5.5 km by ca. 15 Ma. Contrasting precipitation patterns between the Himalaya-Tibet edifice and the Himalaya foreland basin for the past ∼56 m.y. show progressive drying across southern Tibet, seemingly linked to the uplift of the Himalaya orogen.
Temperature and volume of global marine sediments
Authors: LaRowe Douglas E. , Burwicz Ewa , Arndt Sandra , Dale Andrew W. , Amend Jan P.
Published: January 2017

Marine sediments contribute significantly to global element cycles on multiple time scales. This is due in large part to microbial activity in the shallower layers and abiotic reactions resulting from increasing temperatures and pressures at greater depths. Quantifying the rates of these diagenetic changes requires a three-dimensional description of the physiochemical properties of marine sediments. In a step toward reaching this goal, we have combined global data sets describing bathymetry, heat conduction, bottom-water temperatures, and sediment thickness to quantify the three-dimensional distribution of temperature in marine sediments. This model has revealed that ∼35% of sediments are above 60 °C, conditions that are suitable for petroleum generation. Furthermore, significant microbial activity could be inhibited in ∼25% of marine sediments, if 80 °C is taken as a major thermal barrier for subsurface life. In addition to a temperature model, we have calculated new values for the total volume (3.01 × 108 km3) and average thickness (721 m) of marine sediments, and provide the only known determination of the volume of marine-sediment pore water (8.46 × 107 km3), equivalent to ∼6.3% of the volume of the ocean. The results presented here can be used to help quantify the rates of mineral transformations, lithification, catagenesis, and the extent of life in the subsurface on a global scale.
Coupling leeside grainfall to avalanche characteristics in aeolian dune dynamics
Authors: Nield Joanna M. , Wiggs Giles F.S. , Baddock Matthew C. , Hipondoka Martin H.T.
Published: January 2017

Avalanche (grainflow) processes are fundamental drivers of dune morphodynamics and are typically initiated by grainfall accumulations. In sedimentary systems, however, the dynamism between grainfall and grainflow remains unspecified because simple measurements are hampered by the inherent instability of lee slopes. Here, for the first time, terrestrial laser scanning is used to quantify key aspects of the grainfall process on the lee (slip face) of a barchan sand dune. We determine grainfall zone extent and flux and show their variability under differing wind speeds. The increase in the downwind distance from the brink of peak grainfall under stronger winds provides a mechanism that explains the competence of large avalanches to descend the entire lee slope. These findings highlight important interactions between wind speed, grainfall, and subsequent grainflow that influence dune migration rates and are important for correct interpretation of dune stratigraphy.
Effect of Electroacupuncture on the Expression of Agrin and Acetylcholine Receptor Subtypes in Rats with Tibialis Anterior Muscular Atrophy Induced by Sciatic Nerve Injection Injury
Authors: Yu Jianqi , Wang Meng , Liu Junying , Zhang Xiaoming , Yang Shengbo
Published: January 2017

Objective

To investigate the effects of electroacupuncture (EA) on mRNA and protein expression of agrin, acetylcholine receptor (AChR)-ε and AChR-γ in a rat model of tibialis anterior muscle atrophy induced by sciatic nerve injection injury, and to examine the underlying mechanism of action.

Methods

Fifty-four adult Sprague-Dawley rats were divided into four groups: healthy control group (CON, n=6); sciatic nerve injury group (SNI, n=24), comprising rats euthanased at 1, 2, 4 and 6 weeks, respectively, after penicillin injection-induced SNI (n=6 each); CON+EA group (n=12), comprising healthy rats euthanased at 4 and 6 weeks (after 2 and 4 weeks, respectively, of EA at GB30 and ST36); and SNI+EA group, comprising rats euthanased at 4 and 6 weeks (after 2 and 4 weeks, respectively, of EA). The sciatic nerve functional index (SFI), tibialis anterior muscle weight, muscle fibre cross-sectional area (CSA), and changes in agrin, AChR-ε, and AChR-γ expression levels were analysed.

Results

Compared with the control group (CON), SNI rats showed decreased SFI. The weight of the tibialis anterior muscle and muscle fibre CSA decreased initially and recovered slightly over time. mRNA/protein expression of agrin and AChR-ε were downregulated and AChR-γ expression was detectable (vs zero expression in the CON/CON+EA groups). There were no significant differences in CON+EA versus CON groups. However, the SNI+EA group exhibited significant improvements compared with the untreated SNI group (p<0.05).

Conclusions

EA may alleviate tibialis anterior muscle atrophy induced by sciatic nerve injection injury by upregulating agrin and AChR-ε and downregulating AChR-γ.
Successful treatment of Takayasu arteritis with rituximab as a first-line immunosuppressant
Authors: O'Connor Mortimer B , O'Donovan Neil , Bond Ursula , Phelan Mark J
Published: January 2017

Takayasu arteritis is a rare large vessel vasculitis which has traditionally been treated with high-dose steroids. There have been a small number of publications where biological agents have been used to manage refractory cases. To the authors knowledge, there are no publications using biological agents in combination with steroids as a first-line treatment in Takayasu arteritis. In this publication, we document the case of Takayasu arteritis, in a 39-year-old woman, where rituximab was used in combination with steroids as a first-line agent in the setting of poorly controlled bipolar affective disorder.
Benign cystic mediastinal teratoma presenting as a massive pleural effusion in a 17-year–old boy
Authors: Montebello Annalisa , Mizzi Adrian , Cassar Paul John , Cassar Karen
Published: January 2017

Mediastinal teratomas are a rare, albeit an important differential diagnosis of anterior/middle mediastinal masses in young adults and various atypical presentations have been reported. The authors report a case of a 17-year-old boy who presented with a 2-month history of worsening shortness of breath and pleuritic chest pain. A massive left-sided pleural fluid collection was seen on a chest radiograph (CXR). The pleural fluid was drained and a CT Thorax confirmed the presence of a cystic mass. Following re-accumulation of the fluid, thoracotomy was performed and a benign mediastinal teratoma excised. The patient remained well with no evidence of recurrence on follow-up CXRs a year post operatively.
Gambling disorder: a side effect of an off-label prescription of baclofen—literature review
Authors: Guillou-Landreat Morgane , Victorri Vigneau Caroline , Gerardin Marie
Published: January 2017

The use of high-dose baclofen emerged in 2008 in the treatment of alcohol-use disorders. Its prescription is still off-label in France, but recent trials have suggested the interest of using high doses for alcohol dependence, so we have to deal with an increase in its use. However, we still have few data about the adverse effects of a high-dose baclofen prescription, especially in complex addictive disorders. We present a case of a 32-year-old man who sought treatment for gambling disorders (GDs). He had complex addictive disorders, including alcohol-use disorders and GDs. He developed a severe GD, after treatment with a high dose of baclofen. The maximum dose was 160 mg/day, prescribed for his alcohol-use disorders. According to the Naranjo algorithm, the score was +7, it enabled to conclude that problem of gambling was probably imputable to baclofen. We discuss this case with reference to literature.
Successful pregnancy following treatment of recurrent chronic histiocytic intervillositis
Authors: Vardi Leehe , Paterson Helen , Hung Noelyn Anne
Published: January 2017

Chronic histiocytic intervillositis (CHI) is a rare placental lesion associated with adverse obstetric outcomes and high recurrence rate. We report a case of six consecutive pregnancies in one woman, where CHI was detected following an intrauterine death in the fifth pregnancy, after being missed in four earlier losses. The successful sixth pregnancy was treated with a combination of immunosuppressive and antithrombotic agents. While low-molecular-weight heparin (LMWH) and aspirin had been shown to improve pregnancy outcome in recurrent pregnancy loss, there was limited evidence of improved outcome in CHI. It has been suggested that CHI may result from a maternal immunological process and there have been a few reports of the use of corticosteroids because of this possibility, though without convincing evidence of efficacy. We too tried a corticosteroid, in combination with LMWH and aspirin. Comparative histopathological analysis of the placentae supported post-treatment effectiveness of our intervention strategy.
Unexpected complication after radical (inguinal) orchidectomy: trans-sphincteric anoscrotal fistula
Authors: Patel Amit , Gillespie Chris , Kiosoglous Anthony J
Published: January 2017

Anoscrotal fistula is an extremely rare condition involving an epithelialised tract between the anal canal and scrotal wall. It is more commonly seen as a congenital phenomenon in the paediatric population, and has not previously been described in the literature in adults. We present the case of a man aged 52 years who developed a complex anoscrotal fistula after a radical inguinal orchidectomy for an intratesticular seminoma. A postsurgical wound-site infection developed into a chronically discharging wound refractory to antibiotic treatment prompting further investigation. By way of MRI, a 10 cm long trans-sphincteric anoscrotal fistula was found. The patient was successfully treated by fistuloscopic curettage, internal closure using an Ovesco clip, and negative pressure dressing. We present for the first time a rare anoscrotal fistula in an adult.