bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Screen for and Validation of Prodrug Antimicrobials
Authors: Fleck Laura E. , North E. Jeffrey , Lee Richard E. , Mulcahy Lawrence R. , Casadei Gabriele , Lewis Kim 
Published: December 2013

ABSTRACT

The rise of resistant pathogens and chronic infections tolerant to antibiotics presents an unmet need for novel antimicrobial compounds. Identifying broad-spectrum leads is challenging due to the effective penetration barrier of Gram-negative bacteria, formed by an outer membrane restricting amphipathic compounds, and multidrug resistance (MDR) pumps. In chronic infections, pathogens are shielded from the immune system by biofilms or host cells, and dormant persisters tolerant to antibiotics are responsible for recalcitrance to chemotherapy with conventional antibiotics. We reasoned that the dual need for broad-spectrum and sterilizing compounds could be met by developing prodrugs that are activated by bacterium-specific enzymes and that these generally reactive compounds could kill persisters and accumulate over time due to irreversible binding to targets. We report the development of a screen for prodrugs, based on identifying compounds that nonspecifically inhibit reduction of the viability dye alamarBlue, and then eliminate generally toxic compounds by testing for cytotoxicity. A large pilot of 55,000 compounds against
Escherichia coli
produced 20 hits, 3 of which were further examined. One compound, ADC111, is an analog of a known nitrofuran prodrug nitrofurantoin, and its activity depends on the presence of activating enzymes nitroreductases. ADC112 is an analog of another known antimicrobial tilbroquinol with unknown mechanism of action, and ADC113 does not belong to an approved class. All three compounds had a good spectrum and showed good to excellent activity against persister cells in biofilm and stationary cultures. These results suggest that screening for overlooked prodrugs may present a viable platform for antimicrobial discovery.
Population Analysis of Escherichia coli Isolates with Discordant Resistance Levels by Piperacillin-Tazobactam Broth Microdilution and Agar Dilution Testing
Authors: Shubert Carole , Slaughter Jen , Creely David , van Belkum Alex , Gayral Jean Pierre , Dunne William Michael , Zambardi Gilles , Shortridge Dee 
Published: December 2013

ABSTRACT

Population analysis was performed for 42
Escherichia coli
isolates to determine whether heterogeneity of resistance was a factor in piperacillin-tazobactam category differences between agar dilution and broth microdilution. Of 20 isolates discordant between methods, 80% were heterogeneous. Of 22 isolates in agreement, 59% were homogeneous. Heterogeneity and homogeneity rates for those in agreement were significantly different from those that were discordant (
P
value, 0.010). Heterogeneity of resistance expression appears to be an important factor in category differences observed between broth microdilution and agar dilution for piperacillin-tazobactam.
Transcription Factor CCG-8 as a New Regulator in the Adaptation to Antifungal Azole Stress
Authors: Sun Xianyun , Wang Kangji , Yu Xinxu , Liu Jie , Zhang Hanxing , Zhou Fucai , Xie Baogui , Li Shaojie 
Published: December 2013

ABSTRACT

Antifungal azoles are widely used for controlling fungal infections. Fungi are able to change the expression of many genes when they adapt to azole stress, and increased expression of some of these genes can elevate resistance to azoles. However, the regulatory mechanisms behind transcriptional adaption to azoles in filamentous fungi are poorly understood. In this study, we found that deletion of the transcription factor gene
ccg-8
, which is known to be a clock-controlled gene, made
Neurospora crassa
hypersensitive to azoles. A comparative genome-wide analysis of the responses to ketoconazole of the wild type and the
ccg-8
mutant revealed that the transcriptional responses to ketoconazole of 78 of the 488 transcriptionally ketoconazole-upregulated genes and the 427 transcriptionally ketoconazole-downregulated genes in the wild type were regulated by CCG-8. Ketoconazole sensitivity testing of all available knockout mutants for CCG-8-regulated genes revealed that CCG-8 contributed to azole adaption by regulating the ketoconazole responses of many genes, including the target gene (
erg11
), an azole transporter gene (
cdr4
), a hexose transporter gene (
hxt13
), a stress response gene (locus number NCU06317, named
kts-1
), two transcription factor genes (NCU01386 [named
kts-2
] and
fsd-1/ndt80
), four enzyme-encoding genes, and six unknown-function genes. CCG-8 also regulated phospholipid synthesis in
N. crassa
in a manner similar to that of its homolog in
Saccharomyces cerevisiae
, Opi1p. However, there was no cross talk between phospholipid synthesis and azole resistance in
N. crassa
. CCG-8 homologs are conserved and are common in filamentous fungi. Deletion of the CCG-8 homolog-encoding gene in
Fusarium verticillioides
(
Fvccg-8
) also made this fungus hypersensitive to antifungal azoles.
BsaB, a Novel Adherence Factor of Group B Streptococcus
Authors: Jiang Shengmei , Wessels Michael R. 
Published: December 2013

ABSTRACT

Streptococcus agalactiae
(group B
Streptococcus
[GBS]) is a leading cause of neonatal sepsis and meningitis, peripartum infections in women, and invasive infections in chronically ill or elderly individuals. GBS can be isolated from the gastrointestinal or genital tracts of up to 30% of healthy adults, and infection is thought to arise from invasion from a colonized mucosal site. Accordingly, bacterial surface components that mediate attachment of GBS to host cells or the extracellular matrix represent key factors in the colonization and infection of the human host. We identified a conserved GBS gene of unknown function that was predicted to encode a cell wall-anchored surface protein. Deletion of the gene and a cotranscribed upstream open reading frame (ORF) in GBS strain 515 reduced bacterial adherence to VK2 vaginal epithelial cells
in vitro
and reduced GBS binding to fibronectin-coated microtiter wells. Expression of the gene product in
Lactococcus lactis
conferred the ability to adhere to VK2 cells, to fibronectin and laminin, and to fibronectin-coated ME-180 cervical epithelial cells. Expression of the recombinant protein in
L. lactis
also markedly increased biofilm formation. The adherence function of the protein, named
b
acterial
s
urface
a
dhesin of G
B
S (BsaB), depended both on a central BID1 domain found in bacterial intimin-like proteins and on the C-terminal portion of the BsaB protein. Expression of BsaB in GBS, like that of several other adhesins, was regulated by the CsrRS two-component system. We conclude that BsaB represents a newly identified adhesin that participates in GBS attachment to epithelial cells and the extracellular matrix.
Low-Dose Intradermal Infection with Trypanosoma congolense Leads to Expansion of Regulatory T Cells and Enhanced Susceptibility to Reinfection
Authors: Onyilagha Chukwunonso , Okwor Ifeoma , Kuriakose Shiby , Singh Rani , Uzonna Jude 
Published: December 2013

ABSTRACTBALB/c mice are highly susceptible to experimental intraperitonealTrypanosoma congolenseinfection. However, a recent report showed that these mice are relatively resistant to primary intradermal low-dose infection. Paradoxically, repeated low-dose intradermal infections predispose mice to enhanced susceptibility to an otherwise noninfectious dose challenge. Here, we explored the mechanisms responsible for this low-dose-induced susceptibility to subsequent low-dose challenge infection. We found that akin to intraperitoneal infection, low-dose intradermal infection led to production of interleukin-10 (IL-10), IL-6, IL-12, tumor necrosis factor alpha (TNF-α), transforming growth factor β (TGF-β), and gamma interferon (IFN-γ) by spleen and draining lymph node cells. Interestingly, despite the absence of parasitemia, low-dose intradermal infection led to expansion of CD4+CD25+Foxp3+cells (T regulatory cells [Tregs]) in both the spleens and lymph nodes draining the infection site. Depletion of Tregs by anti-CD25 monoclonal antibody (MAb) treatment during primary infection or before challenge infection following repeated low-dose infection completely abolished the low-dose-induced enhanced susceptibility. In addition, Treg depletion was associated with dramatic reduction in serum levels of TGF-β and IL-10. Collectively, these findings show that low-dose intradermal infection leads to rapid expansion of Tregs, and these cells mediate enhanced susceptibility to subsequent infection.
Salmonella enterica Serovar Typhimurium Infection-Induced CD11b+Gr1+Cells Ameliorate Allergic Airway Inflammation
Authors: Ganesh Venkateswaran , Baru Abdul Mannan , Hesse Christina , Friedrich Christin , Glage Silke , Gohmert Melanie , Jänke Christine , Sparwasser Tim 
Published: December 2013

ABSTRACTAllergies are mainly characterized as an unrestrained Th2-biased immune response. Epidemiological data associate protection from allergic diseases with the exposure to certain infectious agents during early stages of life. Modulation of the immune response by pathogens has been considered to be a major factor influencing this protection. Recent evidence indicates that immunoregulatory mechanisms induced upon infection ameliorate allergic disorders. A longitudinal study has demonstrated reduced frequency and incidence of asthma in children who reported a prior infection withSalmonella. Experimental studies involvingSalmonella entericaserovar Typhimurium-infected murine models have confirmed protection from induced allergic airway inflammation; however, the underlying cause leading to this amelioration remains incompletely defined. In this study, we aimed to delineate the regulatory function ofSalmonellaTyphimurium infection in the amelioration of allergic airway inflammation in mice. We observed a significant increase in CD11b+Gr1+myeloid cell populations in mice after infection withS. Typhimurium. Usingin vitroandin vivostudies, we confirmed that these myeloid cells reduce airway inflammation by influencing Th2 cells. Further characterization showed that the CD11b+Gr1+myeloid cells exhibited their inhibitory effect by altering GATA-3 expression and interleukin-4 (IL-4) production by Th2 cells. These results indicate that the expansion of myeloid cells uponS. Typhimurium infection could potentially play a significant role in curtailing allergic airway inflammation. These findings signify the contribution of myeloid cells in preventing Th2-mediated diseases and suggest their possible application as therapeutics.
Chlamydia trachomatis-Infected Epithelial Cells and Fibroblasts Retain the Ability To Express Surface-Presented Major Histocompatibility Complex Class I Molecules
Authors: Kägebein Danny , Gutjahr Melanie , Große Christina , Vogel Annette B. , Rödel Jürgen , Knittler Michael R. 
Published: December 2013

ABSTRACTThe obligate intracellular bacterial pathogenChlamydia trachomatisis the causative agent of a variety of infectious diseases such as trachoma and sexually transmitted diseases. In infected target cells,C. trachomatisreplicates within parasitophorous vacuoles and expresses the protease-like activity factor CPAF. Previous studies have suggested that CPAF degrades the host transcription factors RFX5 and NF-κB p65, which are involved in the regulation of constitutive and inducible expression of major histocompatibility complex class I (MHC I). It was speculated thatChlamydiasuppresses the surface presentation of MHC I in order to evade an effective immune response. Nevertheless, a recent study suggested that RFX5 and NF-κB p65 may not serve as target substrates for CPAF-mediated degradation, raising concerns about the proposed MHC I subversion byChlamydia. Hence, we investigated the direct influence ofChlamydiaon MHC I expression and surface presentation in infected host cells. By using nine different human cells and cell lines infected withC. trachomatis(serovar D or LGV2), we demonstrate that chlamydial infection does not interfere with expression, maturation, transport, and surface presentation of MHC I, suggesting functional antigen processing in bacterium-infected cells. Our findings provide novel insights into the interaction of chlamydiae with their host cells and should be taken into consideration for the design of future therapies and vaccines.
Associations between Cigarette Smoking, Hormone Therapy, and Folate Intake with Incident Colorectal Cancer by TP53 Protein Expression Level in a Population-Based Cohort of Older Women
Authors: Tillmans Lori S. , Vierkant Robert A. , Wang Alice H. , Jewel Samadder N. , Lynch Charles F. , Anderson Kristin E. , French Amy J. , Haile Robert W. , Harnack Lisa J. , Potter John D. , Slager Susan L. , Smyrk Thomas C. , Thibodeau Stephen N. , Cerhan James R. , Limburg Paul J. 
Published: December 2013

Abstract
Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. The TP53 (p53) protein, encoded by the TP53 tumor-suppressor gene that is commonly mutated in colorectal cancer, can be readily assessed to differentiate biologically distinct colorectal cancer subtypes. In this prospective cohort study, we examined CS-, HT-, and FI-associated colorectal cancer risks by TP53 protein expression level among Iowa Women's Health Study (IWHS) participants. The IWHS recruited 41,836 randomly selected Iowa women, ages 55 to 69 years, with a valid driver's license at study entry in 1986. Self-reported exposure variables were assessed at baseline. Incident colorectal cancer cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected and evaluated for TP53 protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between CS, HT, or FI and TP53-defined colorectal cancer subtypes. Informative environmental exposure and protein expression data were available for 492 incident colorectal cancer cases: 222 (45.1%) TP53 negative, 72 (14.6%) TP53 low, and 198 (40.2%) TP53 high. Longer duration (&gt;5 years) of HT was inversely associated with TP53 high colorectal cancers (RR, 0.50; 95% CI, 0.27–0.94). No other statistically significant associations were observed. These data support possible heterogeneous effects from HT on TP53-related pathways of colorectal carcinogenesis in older women. Cancer Epidemiol Biomarkers Prev; 23(2); 350–5. ©2013 AACR.
A Conceptual Lemon: Theta Burst Stimulation to the Left Anterior Temporal Lobe Untangles Object Representation and Its Canonical Color
Authors: Chiou Rocco , Sowman Paul F. , Etchell Andrew C. , Rich Anina N. 
Published: December 2013

Abstract
Object recognition benefits greatly from our knowledge of typical color (e.g., a lemon is usually yellow). Most research on object color knowledge focuses on whether both knowledge and perception of object color recruit the well-established neural substrates of color vision (the V4 complex). Compared with the intensive investigation of the V4 complex, we know little about where and how neural mechanisms beyond V4 contribute to color knowledge. The anterior temporal lobe (ATL) is thought to act as a “hub” that supports semantic memory by integrating different modality-specific contents into a meaningful entity at a supramodal conceptual level, making it a good candidate zone for mediating the mappings between object attributes. Here, we explore whether the ATL is critical for integrating typical color with other object attributes (object shape and name), akin to its role in combining nonperceptual semantic representations. In separate experimental sessions, we applied TMS to disrupt neural processing in the left ATL and a control site (the occipital pole). Participants performed an object naming task that probes color knowledge and elicits a reliable color congruency effect as well as a control quantity naming task that also elicits a cognitive congruency effect but involves no conceptual integration. Critically, ATL stimulation eliminated the otherwise robust color congruency effect but had no impact on the numerical congruency effect, indicating a selective disruption of object color knowledge. Neither color nor numerical congruency effects were affected by stimulation at the control occipital site, ruling out nonspecific effects of cortical stimulation. Our findings suggest that the ATL is involved in the representation of object concepts that include their canonical colors.
The Neural Mechanism Underlying Ordinal Numerosity Processing
Authors: Gebuis Titia , Reynvoet Bert 
Published: December 2013

Abstract
Changes in the sensory properties of numerosity stimuli have a direct effect on the outcomes of nonsymbolic number tasks. This suggests a prominent role of sensory properties in numerosity processing. However, the current consensus holds that numerosity is processed independent of its sensory properties. To investigate the role of sensory cues in ordinal number processes, we manipulated both dimensions orthogonally. Participants passively viewed the stimuli while their brain activity was measured using EEG. The results revealed an interaction between numerosity and its sensory properties in the absence of main effects. Different neural responses were present for trials where numerosity and sensory cues changed in the same direction compared with trials where they changed in opposite directions. These results show that the sensory cues are expected to change in concert with numerosity and support the notion that the visual cues are taken into account when judging numerosity.
Processing Graded Feedback: Electrophysiological Correlates of Learning from Small and Large Errors
Authors: Luft Caroline Di Bernardi , Takase Emilio , Bhattacharya Joydeep 
Published: December 2013

Abstract
Feedback processing is important for learning and therefore may affect the consolidation of skills. Considerable research demonstrates electrophysiological differences between correct and incorrect feedback, but how we learn from small versus large errors is usually overlooked. This study investigated electrophysiological differences when processing small or large error feedback during a time estimation task. Data from high-learners and low-learners were analyzed separately. In both high- and low-learners, large error feedback was associated with higher feedback-related negativity (FRN) and small error feedback was associated with a larger P300 and increased amplitude over the motor related areas of the left hemisphere. In addition, small error feedback induced larger desynchronization in the alpha and beta bands with distinctly different topographies between the two learning groups: The high-learners showed a more localized decrease in beta power over the left frontocentral areas, and the low-learners showed a widespread reduction in the alpha power following small error feedback. Furthermore, only the high-learners showed an increase in phase synchronization between the midfrontal and left central areas. Importantly, this synchronization was correlated to how well the participants consolidated the estimation of the time interval. Thus, although large errors were associated with higher FRN, small errors were associated with larger oscillatory responses, which was more evident in the high-learners. Altogether, our results suggest an important role of the motor areas in the processing of error feedback for skill consolidation.
Love to Win or Hate to Lose? Asymmetry of Dopamine D2 Receptor Binding Predicts Sensitivity to Reward versus Punishment
Authors: Tomer Rachel , Slagter Heleen A. , Christian Bradley T. , Fox Andrew S. , King Carlye R. , Murali Dhanabalan , Gluck Mark A. , Davidson Richard J. 
Published: December 2013

Abstract
Humans show consistent differences in the extent to which their behavior reflects a bias toward appetitive approach-related behavior or avoidance of aversive stimuli [Elliot, A. J. Approach and avoidance motivation. In A. J. Elliot (Ed.), Handbook of approach and avoidance motivation (pp. 3–14). New York: Psychology Press, 2008]. We examined the hypothesis that in healthy participants this motivational bias (assessed by self-report and by a probabilistic learning task that allows direct comparison of the relative sensitivity to reward and punishment) reflects lateralization of dopamine signaling. Using [F-18]fallypride to measure D2/D3 binding, we found that self-reported motivational bias was predicted by the asymmetry of frontal D2 binding. Similarly, striatal and frontal asymmetries in D2 dopamine receptor binding, rather than absolute binding levels, predicted individual differences in learning from reward versus punishment. These results suggest that normal variation in asymmetry of dopamine signaling may, in part, underlie human personality and cognition.
Commonalities for Numerical and Continuous Quantity Skills at Temporo-parietal Junction
Authors: Cappelletti Marinella , Chamberlain Rebecca , Freeman Elliot D. , Kanai Ryota , Butterworth Brian , Price Cathy J. , Rees Geraint 
Published: December 2013

Abstract
How do our abilities to process number and other continuous quantities such as time and space relate to each other? Recent evidence suggests that these abilities share common magnitude processing and neural resources, although other findings also highlight the role of dimension-specific processes. To further characterize the relation between number, time, and space, we first examined them in a population with a developmental numerical dysfunction (developmental dyscalculia) and then assessed the extent to which these abilities correlated both behaviorally and anatomically in numerically normal participants. We found that (1) participants with dyscalculia showed preserved continuous quantity processing and (2) in numerically normal adults, numerical and continuous quantity abilities were at least partially dissociated both behaviorally and anatomically. Specifically, gray matter volume correlated with both measures of numerical and continuous quantity processing in the right TPJ; in contrast, individual differences in number proficiency were associated with gray matter volume in number-specific cortical regions in the right parietal lobe. Together, our new converging evidence of selective numerical impairment and of number-specific brain areas at least partially distinct from common magnitude areas suggests that the human brain is equipped with different ways of quantifying the outside world.