bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delicate Metabolic Control and Coordinated Stress Response Critically Determine Antifungal Tolerance of Candida albicans Biofilm Persisters
Authors: Li Peng , Seneviratne Chaminda J. , Alpi Emanuele , Vizcaino Juan A. , Jin Lijian 
Published: July 2015

ABSTRACT

Candida
infection has emerged as a critical health care burden worldwide, owing to the formation of robust biofilms against common antifungals. Recent evidence shows that multidrug-tolerant persisters critically account for biofilm recalcitrance, but their underlying biological mechanisms are poorly understood. Here, we first investigated the phenotypic characteristics of
Candida
biofilm persisters under consecutive harsh treatments of amphotericin B. The prolonged treatments effectively killed the majority of the cells of biofilms derived from representative strains of
Candida albicans
,
Candida glabrata
, and
Candida tropicalis
but failed to eradicate a small fraction of persisters. Next, we explored the tolerance mechanisms of the persisters through an investigation of the proteomic profiles of
C. albicans
biofilm persister fractions by liquid chromatography-tandem mass spectrometry. The
C. albicans
biofilm persisters displayed a specific proteomic signature, with an array of 205 differentially expressed proteins. The crucial enzymes involved in glycolysis, the tricarboxylic acid cycle, and protein synthesis were markedly downregulated, indicating that major metabolic activities are subdued in the persisters. It is noteworthy that certain metabolic pathways, such as the glyoxylate cycle, were able to be activated with significantly increased levels of isocitrate lyase and malate synthase. Moreover, a number of important proteins responsible for
Candida
growth, virulence, and the stress response were greatly upregulated. Interestingly, the persisters were tolerant to oxidative stress, despite highly induced intracellular superoxide. The current findings suggest that delicate metabolic control and a coordinated stress response may play a crucial role in mediating the survival and antifungal tolerance of
Candida
biofilm persisters.
Epidemiologic Correlates of Pyrazinamide-Resistant Mycobacterium tuberculosis in New York City
Authors: Verdugo Dawn , Fallows Dorothy , Ahuja Shama , Schluger Neil , Kreiswirth Barry , Mathema Barun 
Published: July 2015

ABSTRACT

Pyrazinamide (PZA) has important sterilizing activity in tuberculosis (TB) chemotherapy. We describe trends, risk factors, and molecular epidemiology associated with PZA-resistant (PZA
r
)
Mycobacterium tuberculosis
in New York City (NYC). From 2001 to 2008, all incident culture-positive TB cases reported by the NYC Department of Health and Mental Hygiene (DOHMH) were genotyped by IS
6110
-based restriction fragment length polymorphism and spoligotype. Multidrug-resistant (MDR) isolates underwent DNA sequencing of resistance-determining regions of
pncA
,
rpoB
,
katG
, and
fabG1
. Demographic and clinical information were extracted from the NYC DOHMH TB registry. During this period, PZA
r
doubled (1.6% to 3.6%) overall, accounting for 44% (70/159) of the MDR population and 1.4% (75/5511) of the non-MDR population. Molecular genotyping revealed strong microbial phylogenetic associations with PZA
r
. Clustered isolates and those from acid-fast bacillus (AFB) smear-positive cases had 2.7 (95% confidence interval [CI] = 1.71 to 4.36) and 2.0 (95% CI = 1.19 to 3.43) times higher odds of being PZA
r
, respectively, indicating a strong likelihood of recent transmission. Among the MDR population, PZA
r
was acquired somewhat more frequently via primary transmission than by independent pathways. Our molecular analysis also revealed that several historic
M. tuberculosis
strains responsible for MDR TB outbreaks in the early 1990s were continuing to circulate in NYC. We conclude that the increasing incidence of PZA
r
, with clear microbial risk factors, underscores the importance of routine PZA drug susceptibility testing and
M. tuberculosis
genotyping for the identification, control, and prevention of increasingly resistant organisms.
Age-Stratified Treatment Response Rates in Hospitalized Patients with Clostridium difficile Infection Treated with Metronidazole
Authors: Pham Vy P. , Luce Andrea M. , Ruppelt Sara C. , Wei Wenjing , Aitken Samuel L. , Musick William L. , Roux Ryan K. , Garey Kevin W. 
Published: July 2015

ABSTRACT

Consensus on the optimal treatment of
Clostridium difficile
infection (CDI) is rapidly changing. Treatment with metronidazole has been associated with increased clinical failure rates; however, the reasons for this are unclear. The purpose of this study was to assess age-related treatment response rates in hospitalized patients with CDI treated with metronidazole. This was a retrospective, multicenter cohort study of hospitalized patients with CDI. Patients were assessed for refractory CDI, defined as persistent diarrhea after 7 days of metronidazole therapy, and stratified by age and clinical characteristics. A total of 242 individuals, aged 60 ± 18 years (Charlson comorbidity index, 3.8 ± 2.4; Horn's index, 1.7 ± 1.0) were included. One hundred twenty-eight patients (53%) had severe CDI. Seventy patients (29%) had refractory CDI, a percentage that increased from 22% to 28% and to 37% for patients aged less than 50 years, for patients from 50 to 70 years, and for patients aged >70 years, respectively (
P
= 0.05). In multivariate analysis, Horn's index (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.50 to 2.77;
P
< 0.001), severe CDI (OR, 2.25; 95% CI, 1.15 to 4.41;
P
= 0.018), and continued use of antibiotics (OR, 2.65; 95% CI, 1.30 to 5.39;
P
= 0.0072) were identified as significant predictors of refractory CDI. Age was not identified as an independent risk factor for refractory CDI. Therefore, hospitalized elderly patients with CDI treated with metronidazole had increased refractory CDI rates likely due to increased underlying severity of illness, severity of CDI, and concomitant antibiotic use. These results may help identify patients that may benefit from alternative
C. difficile
treatments other than metronidazole.
Garcinia xanthochymus Benzophenones Promote Hyphal Apoptosis and Potentiate Activity of Fluconazole against Candida albicans Biofilms
Authors: Jackson Desmond N. , Yang Lin , Wu ShiBiao , Kennelly Edward J. , Lipke Peter N. 
Published: July 2015

ABSTRACT

Xanthochymol and garcinol, isoprenylated benzophenones purified from
Garcinia xanthochymus
fruits, showed multiple activities against
Candida albicans
biofilms. Both compounds effectively prevented emergence of fungal germ tubes and were also cytostatic, with MICs of 1 to 3 μM. The compounds therefore inhibited development of hyphae and subsequent biofilm maturation. Xanthochymol treatment of developing and mature biofilms induced cell death. In early biofilm development, killing had the characteristics of apoptosis, including externalization of phosphatidyl serine and DNA fragmentation, as evidenced by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) fluorescence. These activities resulted in failure of biofilm maturation and hyphal death in mature biofilms. In mature biofilms, xanthochymol and garcinol caused the death of biofilm hyphae, with 50% effective concentrations (EC
50
s) of 30 to 50 μM. Additionally, xanthochymol-mediated killing was complementary with fluconazole against mature biofilms, reducing the fluconazole EC
50
from >1,024 μg/ml to 13 μg/ml. Therefore, xanthochymol has potential as an adjuvant for antifungal treatments as well as in studies of fungal apoptosis.
The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei
Authors: Carvalho Luis , Martínez-García Marta , Pérez-Victoria Ignacio , Manzano José Ignacio , Yardley Vanessa , Gamarro Francisco , Pérez-Victoria José M. 
Published: July 2015

ABSTRACT

The protozoan parasite
Trypanosoma brucei
causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different
T. brucei
spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca
2+
, and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant
in vitro
activity against
T. brucei
.
A Toll-Like Receptor 5 Agonist Improves the Efficacy of Antibiotics in Treatment of Primary and Influenza Virus-Associated Pneumococcal Mouse Infections
Authors: Porte Rémi , Fougeron Delphine , Muñoz-Wolf Natalia , Tabareau Julien , Georgel Anne-France , Wallet Fréderic , Paget Christophe , Trottein François , Chabalgoity José A. , Carnoy Christophe , Sirard Jean-Claude 
Published: July 2015

ABSTRACT

Prophylactic intranasal administration of the Toll-like receptor 5 (TLR5) agonist flagellin protects mice against respiratory pathogenic bacteria. We hypothesized that TLR5-mediated stimulation of lung immunity might improve the therapeutic index of antibiotics for the treatment of
Streptococcus pneumoniae
respiratory infections in mice. Intranasal administration of flagellin was combined with either oral administration of amoxicillin or intraperitoneal injection of trimethoprim-sulfamethoxazole to treat
S. pneumoniae
-infected animals. Compared with standalone treatments, the combination of antibiotic and flagellin resulted in a lower bacterial load in the lungs and greater protection against
S. pneumoniae
dissemination and was associated with an early increase in neutrophil infiltration in the airways. The antibiotic-flagellin combination treatment was, however, not associated with any exacerbation of inflammation. Moreover, combination treatment was more efficacious than standalone antibiotic treatments in the context of post-influenza virus pneumococcal infection. Lastly, TLR5 signaling was shown to be mandatory for the efficacy of the combined antibacterial therapy. This report is the first to show that combining antibiotic treatment with the stimulation of mucosal innate immunity is a potent antibacterial strategy against pneumonia.
A Leapfrog Strategy for Pursuit-Evasion in a Polygonal Environment
Authors: Ames Brendan , Beveridge Andrew , Carlson Rosalie , Djang Claire , Isler Volkan , Ragain Stephen , Savage Maxray 
Published: July 2015

We study pursuit-evasion in a polygonal environment with polygonal obstacles. In this turn based game, an evader [Formula: see text] is chased by pursuers [Formula: see text]. The players have full information about the environment and the location of the other players. The pursuers are allowed to coordinate their actions. On the pursuer turn, each [Formula: see text] can move to any point at distance at most 1 from his current location. On the evader turn, he moves similarly. The pursuers win if some pursuer becomes co-located with the evader in finite time. The evader wins if he can evade capture forever. It is known that one pursuer can capture the evader in any simply-connected polygonal environment, and that three pursuers are always sufficient in any polygonal environment [Formula: see text] (possibly with polygonal obstacles). We contribute two new results to this field. First, we fully characterize when an environment with a single obstacle is one-pursuerwin or two-pursuer-win. Second, we give sufficient (but not necessary) conditions for an environment to have a winning strategy for two pursuers. Such environments can be swept by a leapfrog strategy in which the two cops alternately guard/increase the currently controlled area. The running time of this algorithm is [Formula: see text] where [Formula: see text] is the number of vertices, [Formula: see text] is the number of obstacles and [Formula: see text] is the diameter of the polygonal environment [Formula: see text]. More concretely, for an environment with [Formula: see text] vertices, we describe an [Formula: see text] algorithm that (1) determines whether the obstacles are well-separated, and if so, (2) constructs the required partition for a leapfrog strategy.
Improved Grid Map Layout by Point Set Matching
Authors: Eppstein David , van Kreveld Marc , Speckmann Bettina , Staals Frank 
Published: July 2015

Associating the regions of a geographic subdivision with the cells of a grid is a basic operation that is used in various types of maps, like spatially ordered treemaps and Origin-Destination maps (OD maps). In these cases the regular shapes of the grid cells allow easy representation of extra information about the regions. The main challenge is to find an association that allows a user to find a region in the grid quickly. We call the representation of a set of regions as a grid a grid map.We introduce a new approach to solve the association problem for grid maps by formulating it as a point set matching problem: Given two sets [Formula: see text] (the centroids of the regions) and [Formula: see text] (the grid centres) of [Formula: see text] points in the plane, compute an optimal one-to-one matching between [Formula: see text] and [Formula: see text]. We identify three optimisation criteria that are important for grid map layout: maximise the number of adjacencies in the grid that are also adjacencies of the regions, minimise the sum of the distances between matched points, and maximise the number of pairs of points in [Formula: see text] for which the matching preserves the directional relation (SW, NW, etc.). We consider matchings that minimise the [Formula: see text]-distance (Manhattan-distance), the ranked [Formula: see text]-distance, and the [Formula: see text]-distance, since one can expect that minimising distances implicitly helps to fulfill the other criteria.We present algorithms to compute such matchings and perform an experimental comparison that also includes a previous method to compute a grid map. The experiments show that our more global, matching-based algorithm outperforms previous, more local approaches with respect to all three optimisation criteria.
Evolutionary Determinants of Cancer
Authors: Greaves Mel 
Published: July 2015

Abstract
Our understanding of cancer is being transformed by exploring clonal diversity, drug resistance, and causation within an evolutionary framework. The therapeutic resilience of advanced cancer is a consequence of its character as a complex, dynamic, and adaptive ecosystem engendering robustness, underpinned by genetic diversity and epigenetic plasticity. The risk of mutation-driven escape by self-renewing cells is intrinsic to multicellularity but is countered by multiple restraints, facilitating increasing complexity and longevity of species. But our own species has disrupted this historical narrative by rapidly escalating intrinsic risk. Evolutionary principles illuminate these challenges and provide new avenues to explore for more effective control.
Significance: Lifetime risk of cancer now approximates to 50% in Western societies. And, despite many advances, the outcome for patients with disseminated disease remains poor, with drug resistance the norm. An evolutionary perspective may provide a clearer understanding of how cancer clones develop robustness and why, for us as a species, risk is now off the scale. And, perhaps, of what we might best do to achieve more effective control. Cancer Discov; 5(8); 806–20. ©2015 AACR.
Tropical Cyclogenesis due to ITCZ Breakdown: Idealized Numerical Experiments and a Case Study of the Event in July 1988
Authors: Yokota Sho , Niino Hiroshi , Yanase Wataru 
Published: July 2015

Abstract
The mechanism of tropical cyclogenesis due to the breakdown of the intertropical convergence zone (ITCZ breakdown) and the structure of associated vortices are studied by numerical experiments using a nonhydrostatic mesoscale model. First, an idealized numerical experiment, in which a simple initial state without external disturbances is assumed, is performed without cumulus parameterization. A zonally uniform forcing of high sea surface temperature (SST) is imposed to generate an ITCZ-like structure. This “ITCZ” starts to undulate and eventually breaks down to form several tropical cyclones (TCs). These TCs merge and end up with a single TC. The energy budget analysis shows that barotropic instability of the low-level flow associated with the ITCZ is responsible for the genesis of vortices, and TC-scale buoyancy production soon takes over to contribute to the intensification of TCs. Conversion from the cumulus-scale kinetic energy into the TC-scale kinetic energy is found to be insignificant during ITCZ breakdown.
Additional experiments show that the presence of the warm SST belt and an inclusion of the β effect are not essential for the occurrence of ITCZ breakdown. A numerical simulation of ITCZ breakdown over the Pacific Ocean in July 1988 shows that the mechanism of the tropical cyclogenesis is similar to that in the idealized numerical experiments from the viewpoint of the energy budget. Therefore, horizontal shear instability of the low-level flow and TC-scale buoyancy production are generally more essential than mergers of cumulus-scale vortices for the tropical cyclogenesis due to ITCZ breakdown.
Window retrofit strategy for energy saving in existing residences with different thermal characteristics and window sizes
Authors: Ahn Byung-Lip , Kim Jong-Hun , Jang Cheol-Yong , Leigh Seung-Bok , Jeong Hakgeun 
Published: July 2015

An adequate window system is one of the most important retrofit strategies for effective energy conservation of a building, because the U-value and solar heat gain coefficient of windows have enormous impact on the heating and cooling loads of buildings. Therefore, this paper presents methods for improving the energy efficiency of existing residences that have various window sizes and envelope insulations, through a window retrofit using optimal U-value and solar heat gain coefficient values. Furthermore, the window retrofit strategy has been standardized using analysis of the correlation between the properties of the retrofitted window and energy saving rates. The results show that the annual heating and cooling energy demand decreases by 7.9–16.7% when changing the U-value of the windows in a poorly insulated house, and that the relationship between the lower U-value and energy saving is strong for poorly insulated houses regardless of window size. However, for houses with better insulation and larger window sizes, the total energy usage decreases by 18.4–29.7% when the solar heat gain coefficient is lower, and the energy saving effect of the U-value decreases while that of the solar heat gain coefficient increases. Practical application: This study was focused on improving the energy efficiency of existing residences by applying retrofitting technology. By exploration of the contribution of the specific qualities of windows and the thermal envelope (insulation) system of buildings via simulation, it was determined that it is necessary to adjust the U-value and SHGC of retrofitted windows, in relation to the thermal performance and window-wall ratio of an existing residence, to achieve high energy efficiency.
The Lymphatic Malformation Function (LMF) Instrument
Authors: Kirkham Erin M. , Edwards Todd C. , Weaver Edward M. , Balakrishnan Karthik , Perkins Jonathan A. 
Published: July 2015

ObjectiveThe Lymphatic Malformation Function (LMF) instrument is a preliminary parent‐report assessment designed to measure outcomes in children with cervicofacial lymphatic malformation (LM). This study aimed to assess the measurement properties of the LMF, refine it, test criterion validity, and evaluate the test‐retest reliability.Study DesignCross‐sectional.SettingTwo pediatric tertiary referral centers.SubjectsParents of 60 children from 6 months to 15 years old with cervicofacial LM.MethodsParents were recruited via mail and online. The LMF was administered on paper or online initially and again within 21 days. Response distributions and interitem correlations were examined for item reduction. Exploratory factor analysis was conducted on retained items. Cronbach’s α, Spearman correlation, and intraclass correlation (ICC) coefficients were calculated to test internal consistency, criterion validity (compared to stage), and test‐retest reliability, respectively.ResultsOne item was removed due to a floor effect. The response scale was collapsed from a 5‐point scale to a 3‐point scale due to skewness. Six items were discarded due to redundancy (interitem correlations >0.7); 2 items were discarded due to factor loadings <0.4. Exploratory factor analysis revealed a 2‐factor structure explaining 84% of variance, and the domains Signs and Impacts had good internal consistency (all Cronbach’s α >0.80 and <0.90), significant association with stage (P <. 05), and good overall test‐retest reliability (ICC, 0.82).ConclusionThe LMF has been refined into a 12‐item, 2‐domain instrument measuring LM‐specific signs and impacts with internal consistency, criterion validity, and test‐retest reliability.
Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells
Authors: Linley Adam , Krysov Sergey , Ponzoni Maurilio , Johnson Peter W. , Packham Graham , Stevenson Freda K. 
Published: July 2015

Key PointsUnusual sugars on the tips of sIg of FL cells interact with a tissue lectin to activate tumor-specific signaling. Activating lectin does not allow endocytosis of sIg, leading to persistent, essential, and targetable antigen-independent stimulation.
Salvage Surgery After Chemoradiotherapy in the Management of Esophageal Cancer: Is It a Viable Therapeutic Option?
Authors: Markar Sheraz , Gronnier Caroline , Duhamel Alain , Pasquer Arnaud , Théreaux Jérémie , du Rieu Mael Chalret , Lefevre Jérémie H. , Turner Kathleen , Luc Guillaume , Mariette Christophe 
Published: July 2015

Purpose The aim of this large multicenter study was to assess the impact of salvage esophagectomy after definitive chemoradiotherapy (SALV) on clinical outcome. Patients and Methods Data from consecutive adult patients undergoing resection for esophageal cancer in 30 European centers from 2000 to 2010 were collected. First, groups undergoing SALV (n = 308) and neoadjuvant chemoradiotherapy followed by planned esophagectomy (NCRS; n = 540) were compared. Second, patients who benefited from SALV for persistent (n = 234) versus recurrent disease (n = 74) were compared. Propensity score matching and multivariable analyses were used to compensate for differences in some baseline characteristics. Results SALV versus NCRS groups: In-hospital mortality was similar in both groups (8.4% v 9.3%). The only significant differences in complications were seen for anastomotic leak (17.2% v 10.7%; P = .007) and surgical site infection, which were both more frequent in the SALV group. At 3 years, groups had similar overall (43.3% v 40.1%; P = .542) and disease-free survival (39.2% v 32.8%; P = .232) after matching, along with a similar recurrence pattern. Persistent versus recurrent disease groups: There were no significant differences between groups in incidence of in-hospital mortality or major complications. At 3 years, overall (40.9% v 56.2%; P = .046) and disease-free survival (36.6% v 51.6%; P = .095) were lower in the persistent disease group. Conclusion The results of this large multicenter study from the modern era suggest that SALV can offer acceptable short- and long-term outcomes in selected patients at experienced centers. Persistent cancer after definitive chemoradiotherapy seems to be more biologically aggressive, with poorer survival compared with recurrent cancer.