bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redefining Escherichia coli σ
70
Promoter Elements: −15 Motif as a Complement of the −10 Motif
Authors: Djordjevic Marko 
Published: September 2011

ABSTRACT

Classical elements of σ
70
bacterial promoters include the −35 element (
−35
TTGACA
−30
), the −10 element (
−12
TATAAT
−7
), and the extended −10 element (
−15
TG
−14
). Although the −35 element, the extended −10 element, and the upstream-most base in the −10 element (
−12
T) interact with σ
70
in double-stranded DNA (dsDNA) form, the downstream bases in the −10 motif (
−11
ATAAT
−7
) are responsible for σ
70
-single-stranded DNA (ssDNA) interactions. In order to directly reflect this correspondence, an extension of the extended −10 element to a so-called −15 element (
−15
TGnT
−12
) has been recently proposed. I investigated here the sequence specificity of the proposed −15 element and its relationship to other promoter elements. I found a previously undetected significant conservation of
−13
G and a high degeneracy at
−15
T. I therefore defined the −15 element as a degenerate motif, which, together with the conserved stretch of sequence between −15 and −12, allows treating this element analogously to −35 and −10 elements. Furthermore, the strength of the −15 element inversely correlates with the strengths of the −35 element and −10 element, whereas no such complementation between other promoter elements was found. Despite the direct involvement of −15 element in σ
70
-dsDNA interactions, I found a significantly stronger tendency of this element to complement weak −10 elements that are involved in σ
70
-ssDNA interactions. This finding is in contrast to the established view, according to which the −15 element provides a sufficient number of σ
70
-dsDNA interactions, and suggests that the main parameter determining a functional promoter is the overall promoter strength.
The Ax21 Protein Is a Cell-Cell Signal That Regulates Virulence in the Nosocomial Pathogen Stenotrophomonas maltophilia
Authors: McCarthy Yvonne , Dow J. Maxwell , Ryan Robert P. 
Published: September 2011

ABSTRACT

Stenotrophomonas maltophilia
encodes proteins related to the Rax proteins of
Xanthomonas oryzae
, which are required for the synthesis and secretion of the Ax21 protein. Here we show that Ax21 acts as a cell-cell signal to regulate a diverse range of functions, including virulence, in this nosocomial pathogen.
Identification and Functional Analysis of CT069 as a Novel Transcriptional Regulator in Chlamydia
Authors: Akers Johnny C. , HoDac HoangMinh , Lathrop Richard H. , Tan Ming 
Published: September 2011

ABSTRACT

Only a small number of transcription factors have been predicted in
Chlamydia
spp., which are obligate intracellular bacteria that include a number of important human pathogens. We used a bioinformatics strategy to identify novel transcriptional regulators from the
Chlamydia trachomatis
genome by predicting proteins with the general structure and characteristic functional domains of a bacterial transcription factor. With this approach, we identified CT069 as a candidate transcription factor with sequence similarity at its C terminus to
Treponema pallidum
TroR. Like TroR, the gene for CT069 belongs to an operon that encodes components of a putative ABC transporter for importing divalent metal cations. However, CT069 has been annotated as YtgC because of sequence similarity at its N terminus to TroC, a transmembrane component of this metal ion transporter. Instead, CT069 appears to be a fusion protein composed of YtgC and a TroR ortholog that we have called YtgR. Although it has not been previously reported, a similar YtgC-YtgR fusion protein is predicted to be encoded by other
Chlamydia
spp. and several other bacteria, including
Bacillus subtilis
. We show that recombinant YtgR polypeptide bound specifically to an operator sequence upstream of the
ytg
operon and that binding was enhanced by Zn
2+
. We also demonstrate that YtgR repressed transcription from the
ytg
promoter in a heterologous
in vivo
reporter assay. These results provide evidence that CT069 is a negative regulator of the
ytg
operon, which encodes a putative metal ion transporter in
C. trachomatis
.
Oxygen Is a Master Regulator of the Immunogenicity of Primary Human Glioma Cells
Authors: Olin Michael R. , Andersen Brian M. , Litterman Adam J. , Grogan Patrick T. , Sarver Aaron L. , Robertson Paul T. , Liang Xueqing , Chen Wei , Parney Ian F. , Hunt Matthew A. , Blazar Bruce R. , Ohlfest John R. 
Published: September 2011

Abstract
With recent approval of the first dendritic cell (DC) vaccine for patient use, many other DC vaccine approaches are now being tested in clinical trials. Many of these DC vaccines employ tumor cell lysates (TL) generated from cells cultured in atmospheric oxygen (∼20% O2) that greatly exceeds levels found in tumors in situ. In this study, we tested the hypothesis that TLs generated from tumor cells cultured under physiologic oxygen (∼5% O2) would be more effective as a source for DC antigens. Gene expression patterns in primary glioma cultures established at 5% O2 more closely paralleled patient tumors in situ and known immunogenic antigens were more highly expressed. DCs treated with TLs generated from primary tumor cells maintained in 5% O2 took up and presented antigens to CD8 T cells more efficiently. Moreover, CD8 T cells primed in this manner exhibited superior tumoricidal activity against target cells cultured in either atmospheric 20% O2 or physiologic 5% O2. Together, these results establish a simple method to greatly improve the effectiveness of DC vaccines in stimulating the production of tumoricidal T cells, with broad implications for many of the DC-based cancer vaccines being developed for clinical application. Cancer Res; 71(21); 6583–9. ©2011 AACR.
A Kinome-Wide Screen Identifies the Insulin/IGF-I Receptor Pathway as a Mechanism of Escape from Hormone Dependence in Breast Cancer
Authors: Fox Emily M. , Miller Todd W. , Balko Justin M. , Kuba Maria G. , Sánchez Violeta , Smith R. Adam , Liu Shuying , González-Angulo Ana María , Mills Gordon B. , Ye Fei , Shyr Yu , Manning H. Charles , Buck Elizabeth , Arteaga Carlos L. 
Published: September 2011

Abstract
Estrogen receptor α (ER)–positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER+ breast cancer cells resistant to long-term estrogen deprivation (LTED). A kinome-wide siRNA screen showed that the insulin receptor (InsR) is required for growth of MCF-7/LTED cells. Knockdown of InsR and/or insulin-like growth factor-I receptor (IGF-IR) inhibited growth of 3 of 4 LTED cell lines. Inhibition of InsR and IGF-IR with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone-independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K/AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-IR monoclonal antibody MAB391 was ineffective. Combined treatment with OSI-906 and the ER downregulator fulvestrant more effectively suppressed hormone-independent tumor growth than either drug alone. Finally, an insulin/IGF-I gene expression signature predicted recurrence-free survival in patients with ER+ breast cancer treated with the antiestrogen tamoxifen. We conclude that therapeutic targeting of both InsR and IGF-IR should be more effective than targeting IGF-IR alone in abrogating resistance to endocrine therapy in breast cancer. Cancer Res; 71(21); 6773–84. ©2011 AACR.
A Phase I Study of PF-04929113 (SNX-5422), an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Patients with Refractory Solid Tumor Malignancies and Lymphomas
Authors: Rajan Arun , Kelly Ronan J. , Trepel Jane B. , Kim Yeong Sang , Alarcon Sylvia V. , Kummar Shivaani , Gutierrez Martin , Crandon Sonja , Zein Wadih M. , Jain Lokesh , Mannargudi Baskar , Figg William D. , Houk Brett E. , Shnaidman Michael , Brega Nicoletta , Giaccone Giuseppe 
Published: September 2011

Abstract
Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas.
Methods: This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response.
Results: Thirty-three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m2 administered orally twice a week. One DLT (nonseptic arthritis) was noted. No grade 4 drug-related adverse events were seen; grade 3 adverse events included diarrhea (9%), nonseptic arthritis (3%), aspartate aminotransferase elevation (3%), and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. Pharmacokinetic data revealed rapid absorption, hepatic, and extrahepatic clearance, extensive tissue binding, and almost linear pharmacokinetics of the active drug PF-04928473. Pharmacodynamic studies confirmed inhibition of Hsp90 and a linear correlation between pharmacokinetic parameters and Hsp70 induction.
Conclusions: PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90. No objective responses were seen, but long-lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study, the development of PF-04929113 has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study. Clin Cancer Res; 17(21); 6831–9. ©2011 AACR.
Characteristics and Outcome After Hospitalization for Acute Right Heart Failure in Patients With Pulmonary Arterial Hypertension
Authors: Haddad François , Peterson Tyler , Fuh Eric , Kudelko Kristina T. , de Jesus Perez Vinicio , Skhiri Mehdi , Vagelos Randall , Schnittger Ingela , Denault Andre Y. , Rosenthal David N. , Doyle Ramona L. , Zamanian Roham T. 
Published: September 2011

Background—
Although much is known about the risk factors for poor outcome in patients hospitalized with acute heart failure and left ventricular dysfunction, much less is known about the syndrome of acute heart failure primarily affecting the right ventricle (acute right heart failure).

Methods and Results—

By using Stanford Hospital's pulmonary hypertension database, we identified consecutive acute right heart failure hospitalizations in patients with PAH. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients by 90 days of admission. Multivariable analysis identified a higher respiratory rate on admission (>20 breaths per minute; OR, 3.4; 95% CI, 1.5–7.8), renal dysfunction on admission (glomerular filtration rate <45 mL/min per 1.73 m
2
; OR, 2.7; 95% CI, 1.2–6.3), hyponatremia (serum sodium ≤136 mEq/L; OR, 3.6; 95% CI, 1.7–7.9), and tricuspid regurgitation severity (OR, 2.5 per grade; 95% CI, 1.2–5.5) as independent factors associated with an increased likelihood of death or urgent transplantation.

Conclusions—
These results highlight the high mortality after hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or the need for urgent transplantation in patients with PAH.
Strain rate effects in the indentation behavior of foam-based sandwich structures
Authors: Hassan M , Cantwell W J 
Published: September 2011

Indentation tests have been undertaken at quasi-static and impact rates of strain on sandwich structures based on six different types of polymer foam core and two types of composite skin. Initially, the influence of strain rate on the compression properties of the sandwich structures has been investigated, where it has been shown that the plastic collapse strength of the foam cores is rate sensitive, increasing by approximately 100% over the range of strain rates considered. The indentation behavior of the sandwich structures was characterized using a Meyer indentation law of the form P = Cαn, where P is the applied force, α is the resulting indentation, and C, the contact stiffness and n, the indentation exponent, are constants for a given system. It has been shown that the value of the exponent, n, does not vary significantly with the properties of the core or the skin, typically being close to unity for all tests. The contact stiffness C varied greatly and was found to depend on the plastic collapse strength of the foam and the properties of the skin. It has been shown that a plot of C vs. plastic collapse strength containing all of the quasi-static and dynamic data appears to yield a unique relationship for the systems considered here. Tests have also shown that C varies with indentor radius, with the greatest sensitivity to indentor radius being observed in the higher modulus foams. These results highlight the importance of using the appropriate dynamic contact properties when modeling the impact response of foam-based sandwich structures.
Transient nonverbal learning disorder in a child suffering from Familial Hemiplegic Migraine
Authors: Podestà Barbara , Briatore Eleonora , Boghi Andrea , Marenco Daniela , Calzolari Stefano 
Published: September 2011

Objective: To study the link between nonverbal learning disorder and right cerebral hemisphere dysfunction due to migraine attack in a case of Familial Hemiplegic Migraine. Background: Familial Hemiplegic Migraine can cause neuropsychological deficits besides the motor ones. The nonverbal learning disorder is thought to be caused by a right hemisphere dysfunction. Methods: We describe a child with Familial Hemiplegic Migraine type 2 who showed a transient neuropsychological impairment featuring a nonverbal learning disorder during and after a Hemiplegic migraine attack. Results: Clinical and neuropsychological data showed a nonverbal learning disorder. A mutation in the ATP1A2 gene on chromosome 1q23 was found. Symptoms of nonverbal learning disorder outlasted the left hemiparesis. Two months later he showed a full recovery. Neurophysiological and neuroradiological evaluations were congruent with clinical course and with right hemisphere involvement. Conclusion: The link between nonverbal learning disorder and right cerebral hemisphere dysfunction due to migraine attack is confirmed. Familial Hemiplegic Migraine can cause transient complex neuropsychological syndromes that can be overlooked if not appropriately investigated.
Gender-related differences in functional connectivity in multiple sclerosis
Authors: Schoonheim Menno M , Hulst Hanneke E , Landi Doriana , Ciccarelli Olga , Roosendaal Stefan D , Sanz-Arigita Ernesto J , Vrenken Hugo , Polman Chris H , Stam Cornelis J , Barkhof Frederik , Geurts Jeroen JG 
Published: September 2011

Background: Gender effects are strong in multiple sclerosis (MS), with male patients showing a worse clinical outcome than female patients. Functional reorganization of neural activity may contribute to limit disability, and possible gender differences in this process may have important clinical implications. Objectives: The aim of this study was to explore gender-related changes in functional connectivity and network efficiency in MS patients. Additionally, we explored the association of functional changes with cognitive function. Methods: Sixty subjects were included in the study, matched for age, education level and intelligence quotient (IQ). Male and female patients were matched for disability, disease duration and white matter lesion load. Two cognitive domains often impaired in MS, i.e. visuospatial memory and information processing speed, were evaluated in all subjects. Functional connectivity between brain regions and network efficiency was explored using resting-state functional magnetic resonance imaging and graph analysis. Differences in cognitive and functional characteristics between groups, and correlations with cognitive performance, were examined. Results: Male patients showed worse performance on cognitive tests than female and male controls, while female patients were cognitively normal. Decreases in functional connectivity and network efficiency, observed in male patients, correlated with reduced visuospatial memory ( r = −0.6 and r = −0.5, respectively). In the control group, no cognitive differences were found between genders, despite differences in functional connectivity between healthy men and women. Conclusions: Functional connectivity differences were found in male patients only and were related to impaired visuospatial memory. These results underline the importance of gender in MS and require further investigation in larger and longitudinal studies.
The conversion from sensation to symptom – the case of catarrh, a qualitative study
Authors: Cathcart Russell A , Wilson Janet A , May Carl 
Published: September 2011

Objective: There is significant variation in symptom tolerance before seeking healthcare advice and it has recently been postulated that there may be a similar variation in the degree to which individuals tolerate deviations in physiological body sensations before considering them symptoms. This study looked to explore this transition from sensation to symptom more closely using the clinical entity of chronic catarrh – a frequently presenting problem which represents a putative alteration of a physiological process. Design: Qualitative study using semi-structured interviews. Participants: 19 adult patients presenting with chronic catarrh, persistent throat clearing or post-nasal drip. Setting: Secondary care institute in North of England. Results: Subjects’ accounts revealed three changes in perception of nasopharyngeal mucus that triggered the transition from sensation to symptom: an apparent change in viscosity, quantity, or constancy. Such changes were invariably deemed to have a consequence (threat to wellbeing, social impact, or source of frustration) and invariably drew a response from the sufferer to limit these consequences. Conclusions: Symptoms representing an aberration of normal body sensations likely develop over time in a series of recognizable phases. Discriminatory markers appear to exist which delineate those body sensations accepted and those considered symptoms. These are discussed with the use of a novel symptom evolution pathway diagram.
Loss of the wild-type allele contributes to myeloid expansion and disease aggressiveness in FLT3/ITD knockin mice
Authors: Li Li , Bailey Emily , Greenblatt Sarah , Huso David , Small Donald 
Published: September 2011

AbstractClinical evidence has shown that FLT3 internal tandem duplication (ITD) mutation confers poor prognosis in acute myeloid leukemia. Loss of the FLT3 wild-type (WT) allele is associated with even worse prognosis. We have previously reported that heterozygous FLT3wt/ITD “knockin” mice develop a slowly fatal myeloproliferative neoplasm (MPN). To study the roles of the WT FLT3 and ITD alleles in the development of MPNs, we generated FLT3/ITD homozygous (FLT3ITD/ITD) and hemizygous (FLT3−/ITD) mice. FLT3−/ITD mice, with the loss of WT allele, display a more severe MPN, as evidenced by even larger spleen, higher white blood cell counts, and shorter survival, compared with FLT3wt/ITD mice. Reintroduction of the WT FLT3 allele into FLT3−/ITD BM slowed the progression of MPN in recipient mice. FLT3ITD/ITD mice had an even severe MPN compared with the FLT3−/ITD and FLT3wt/ITD mice. Spontaneous leukemia developed in a small fraction of the FLT3ITD/ITD mice but was never observed in the FLT3−/ITD and FLT3wt/ITD mice. Our results suggest that loss of the WT allele contributes to the development of a more severe phenotype. Thus, the WT FLT3 allele seemingly functions as a tumor suppressor, attenuating the function of the FLT3/ITD allele in leukemia harboring FLT3/ITD mutations.
FcRL4 acts as an adaptive to innate molecular switch dampening BCR signaling and enhancing TLR signaling
Authors: Sohn Hae Won , Krueger Peter D. , Davis Randall S. , Pierce Susan K. 
Published: September 2011

AbstractFc receptor–like 4 (FcRL4) is expressed on the surface of a subset of memory B cells (MBCs) located at sites of invading pathogens in mucosal lymphoid tissues in healthy individuals. Recently, FcRL4+ MBCs were shown to be greatly increased in number in the peripheral blood of HIV-infected viremic individuals, in whom they are associated with B-cell exhaustion, and in individuals chronically reinfected with malaria. In the present study, we provide evidence that the expression of FcRL4 in human B-cell lines disrupts immune synapse formation and blocks antigen-induced BCR signaling at the point of Syk phosphorylation, blocking downstream activation of PLC-γ2 and Vav and the induction of calcium responses and CD69 expression. FcRL4 functions by ligation-independent mechanisms that require the 3 tyrosine residues in its cytoplasmic domain and involves its phosphorylation and association with the tyrosine phosphatases SHP-1 and SHP-2. Remarkably, FcRL4 is concentrated in endosomes after treatment with the TLR9 agonist CpG and enhances signaling through TLR9, as measured by increased expression of CD23. These findings suggest that FcRL4 may act as a molecular switch in B cells to dampen adaptive immune signaling and enhance innate signaling in response to chronic antigenic stimulation.