bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of spiking activity on cortical local field potentials
Authors: Waldert Stephan , Lemon Roger N. , Kraskov Alexander 
Published: August 2013

Key points
The intra‐cortical local field potential (LFP) reflects a variety of electrophysiological processes and is a fundamental signal used to enhance knowledge about neuroscience.
For most investigations, spike‐free LFPs are mandatory for valid conclusions, but spikes can contaminate LFPs and falsify findings despite low‐pass filtering or other attempts to remove spiking activity from LFPs. The extent of this fundamental problem remains unclear.
Using spikes recorded in the awake monkey, we revealed how spike amplitude, spike duration, firing rate and noise statistic influence the extent to which spikes contaminate LFPs.
Contamination varies with these parameters and can affect LFPs down to around 10 Hz; below this it is theoretically possible but unlikely. LFP frequencies up to the (high‐) gamma band can remain unaffected, but signals above must always be carefully analysed.
We propose a method to reveal modulations in spectrograms, which also allows the detection of spike contamination, and provide a systematic guide to assess spike contamination of intra‐cortical LFPs.
Abstract  The intra‐cortical local field potential (LFP) reflects a variety of electrophysiological processes including synaptic inputs to neurons and their spiking activity. It is still a common assumption that removing high frequencies, often above 300 Hz, is sufficient to exclude spiking activity from LFP activity prior to analysis. Conclusions based on such supposedly spike‐free LFPs can result in false interpretations of neurophysiological processes and erroneous correlations between LFPs and behaviour or spiking activity. Such findings might simply arise from spike contamination rather than from genuine changes in synaptic input activity. Although the subject of recent studies, the extent of LFP contamination by spikes is unclear, and the fundamental problem remains. Using spikes recorded in the motor cortex of the awake monkey, we investigated how different factors, including spike amplitude, duration and firing rate, together with the noise statistic, can determine the extent to which spikes contaminate intra‐cortical LFPs. We demonstrate that such contamination is realistic for LFPs with a frequency down to ∼10 Hz. For LFP activity below ∼10 Hz, such as movement‐related potential, contamination is theoretically possible but unlikely in real situations. Importantly, LFP frequencies up to the (high‐) gamma band can remain unaffected. This study shows that spike–LFP crosstalk in intra‐cortical recordings should be assessed for each individual dataset to ensure that conclusions based on LFP analysis are valid. To this end, we introduce a method to detect and to visualise spike contamination, and provide a systematic guide to assess spike contamination of intra‐cortical LFPs.
Activity‐dependent downregulation of D‐type K+ channel subunit Kv1.2 in rat hippocampal CA3 pyramidal neurons
Authors: Hyun Jung Ho , Eom Kisang , Lee Kyu‐Hee , Ho Won‐Kyung , Lee Suk‐Ho 
Published: August 2013

Key points
The intrinsic excitability of a hippocampal CA3 pyramidal cell (CA3‐PC), but not CA1‐PC, is enhanced by repetitive somatic firing at a physiologically relevant frequency (10 Hz for 2 s).
Such an excitability change is mediated by the Ca2+‐ and Src family kinase‐dependent endocytosis of D‐type K+ channel subunit Kv1.2.
We provide evidence that the surface expression of D‐type K+ channels is higher in the distal apical dendrites than in the proximal apical dendrites in CA3‐PCs.
These results help us understand neuronal computational mechanisms underlying the cognitive functions of the hippocampal CA3 area.
Abstract  The intrinsic excitability of neurons plays a critical role in the encoding of memory at Hebbian synapses and in the coupling of synaptic inputs to spike generation. It has not been studied whether somatic firing at a physiologically relevant frequency can induce intrinsic plasticity in hippocampal CA3 pyramidal cells (CA3‐PCs). Here, we show that a conditioning train of 20 action potentials (APs) at 10 Hz causes a persistent reduction in the input conductance and an acceleration of the AP onset time in CA3‐PCs, but not in CA1‐PCs. Induction of such long‐term potentiation of intrinsic excitability (LTP‐IE) was accompanied by a reduction in the D‐type K+ current, and was abolished by the inhibition of endocytosis or protein tyrosine kinase (PTK). Consistently, the CA3‐PCs from Kv1.2 knock‐out mice displayed no LTP‐IE with the same conditioning. Furthermore, the induction of LTP‐IE depended on the back‐propagating APs (bAPs) and intact distal apical dendrites. These results indicate that LTP‐IE is mediated by the internalization of Kv1.2 channels from the distal regions of apical dendrites, which is triggered by bAP‐induced dendritic Ca2+ signalling and the consequent activation of PTK.
Tracking pulmonary gas exchange by breathing control during exercise: role of muscle blood flow
Authors: Haouzi Philippe 
Published: August 2013

AbstractPopulations of group III and IV muscle afferent fibres located in the adventitia of the small vessels appear to respond to the level of venular distension and to recruitment of the vascular bed within the skeletal muscles. The CNS could thus be informed on the level of muscle hyperaemia when the metabolic rate varies. As a result, the magnitude and kinetics of the change in peripheral gas exchange – which translates into pulmonary gas exchange – can be sensed. We present the view that the respiratory control system uses these sources of information of vascular origin, among the numerous inputs produced by exercise, as a marker of the metabolic strain imposed on the circulatory and the ventilatory systems, resulting in an apparent matching between pulmonary gas exchange and alveolar ventilation.
Vibrio cholerae ToxR Downregulates Virulence Factor Production in Response to Cyclo(Phe-Pro)
Authors: Bina X. Renee , Taylor Dawn L. , Vikram Amit , Ante Vanessa M. , Bina James E. 
Published: August 2013

ABSTRACT

Vibrio cholerae
is an aquatic organism that causes the severe acute diarrheal disease cholera. The ability of
V. cholerae
to cause disease is dependent upon the production of two critical virulence determinants, cholera toxin (CT) and the toxin-coregulated pilus (TCP). The expression of the genes that encode for CT and TCP production is under the control of a hierarchical regulatory system called the ToxR regulon, which functions to activate virulence gene expression in response to
in vivo
stimuli. Cyclic dipeptides have been found to be produced by numerous bacteria, yet their biological function remains unknown.
V. cholerae
has been shown to produce cyclo(Phe-Pro). Previous studies in our laboratory demonstrated that cyclo(Phe-Pro) inhibited
V. cholerae
virulence factor production. For this study, we report on the mechanism by which cyclo(Phe-Pro) inhibited virulence factor production. We have demonstrated that exogenous cyclo(Phe-Pro) activated the expression of
leuO
, a LysR-family regulator that had not been previously associated with
V. cholerae
virulence. Increased
leuO
expression repressed
aphA
transcription, which resulted in downregulation of the ToxR regulon and attenuated CT and TCP production. The cyclo(Phe-Pro)-dependent induction of
leuO
expression was found to be dependent upon the virulence regulator ToxR. Cyclo(Phe-Pro) did not affect
toxR
transcription or ToxR protein levels but appeared to enhance the ToxR-dependent transcription of
leuO
. These results have identified
leuO
as a new component of the ToxR regulon and demonstrate for the first time that ToxR is capable of downregulating virulence gene expression in response to an environmental cue.

IMPORTANCE
The ToxR regulon has been a focus of cholera research for more than three decades. During this time, a model has emerged wherein ToxR functions to activate the expression of
Vibrio cholerae
virulence factors upon host entry.
V. cholerae
and other enteric bacteria produce cyclo(Phe-Pro), a cyclic dipeptide that we identified as an inhibitor of
V. cholerae
virulence factor production. This finding suggested that cyclo(Phe-Pro) was a negative effector of virulence factor production and represented a molecule that could potentially be exploited for therapeutic development. In this work, we investigated the mechanism by which cyclo(Phe-Pro) inhibited virulence factor production. We found that cyclo(Phe-Pro) signaled through ToxR to activate the expression of
leuO
, a new virulence regulator that functioned to repress virulence factor production. Our results have identified a new arm of the ToxR regulon and suggest that ToxR may play a broader role in pathogenesis than previously known.
The Molecular Mechanisms of Allosteric Mutations Impairing MepR Repressor Function in Multidrug-Resistant Strains of Staphylococcus aureus
Authors: Birukou Ivan , Tonthat Nam K. , Seo Susan M. , Schindler Bryan D. , Kaatz Glenn W. , Brennan Richard G. 
Published: August 2013

ABSTRACT

Overexpression of the
Staphylococcus aureus
multidrug efflux pump MepA confers resistance to a wide variety of antimicrobials.
mepA
expression is controlled by MarR family member MepR, which represses
mepA
and autorepresses its own production. Mutations in
mepR
are a primary cause of
mepA
overexpression in clinical isolates of multidrug-resistant
S. aureus
. Here, we report crystal structures of three multidrug-resistant MepR variants, which contain the single-amino-acid substitution A103V, F27L, or Q18P, and wild-type MepR in its DNA-bound conformation. Although each mutation impairs MepR function by decreasing its DNA binding affinity, none is located in the DNA binding domain. Rather, all are found in the linker region connecting the dimerization and DNA binding domains. Specifically, the A103V substitution impinges on F27, which resolves potential steric clashes via displacement of the DNA binding winged-helix-turn-helix motifs that lead to a 27-fold reduction in DNA binding affinity. The F27L substitution forces F104 into an alternative rotamer, which kinks helix 5, thereby interfering with the positioning of the DNA binding domains and decreasing
mepR
operator affinity by 35-fold. The Q18P mutation affects the MepR structure and function most significantly by either creating kinks in the middle of helix 1 or completely unfolding its C terminus. In addition, helix 5 of Q18P is either bent or completely dissected into two smaller helices. Consequently, DNA binding is diminished by 2,000-fold. Our structural studies reveal heretofore-unobserved allosteric mechanisms that affect repressor function of a MarR family member and result in multidrug-resistant
Staphylococcus aureus
.

IMPORTANCE
Staphylococcus aureus
is a major health threat to immunocompromised patients.
S. aureus
multidrug-resistant variants that overexpress the multidrug efflux pump
mepA
emerge frequently due to point mutations in MarR family member MepR, the
mepA
transcription repressor. Significantly, the majority of MepR mutations identified in these
S. aureus
clinical isolates are found not in the DNA binding domain but rather in a linker region, connecting the dimerization and DNA binding domains. The location of these mutants underscores the critical importance of a properly functioning allosteric mechanism that regulates MepR function. Understanding the dysregulation of such allosteric MepR mutants underlies this study. The high-resolution structures of three such allosteric MepR mutants reveal unpredictable conformational consequences, all of which preclude cognate DNA binding, while biochemical studies emphasize their debilitating effects on DNA binding affinity. Hence, mutations in the linker region of MepR and their structural consequences are key generators of multidrug-resistant
Staphylococcus aureus
.
Fc Gamma Receptor 3A Polymorphism and Risk for HIV-Associated Cryptococcal Disease
Authors: Rohatgi Soma , Gohil Shruti , Kuniholm Mark H. , Schultz Hannah , Dufaud Chad , Armour Kathryn L. , Badri Sheila , Mailliard Robbie B. , Pirofski Liise-anne 
Published: August 2013

ABSTRACT

Cryptococcus neoformans
is one of the most common causes of fungal disease in HIV-infected persons, but not all of those who are infected develop cryptococcal disease (CD). Although CD4
+
T cell deficiency is a risk factor for HIV-associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, we performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS): 55 who were HIV infected and developed CD and a matched control group of 54 who were HIV infected and 55 who were HIV uninfected. Using additive and allelic statistical models for analysis, the high-affinity FCGR3A 158V allele was significantly associated with CD status after adjusting for race/ethnicity (odds ratio [OR], 2.1;
P
= 0.005), as was the FCGR3A 158 VV homozygous genotype after adjusting for race/ethnicity, rate of CD4
+
T cell decline, and nadir CD4
+
T cell count (OR, 21;
P
= 0.005). No associations between CD and FCGR2A 131 H/R polymorphism were identified. In binding studies, human IgG (hIgG)-
C. neoformans
complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F, and in cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more
C. neoformans
-infected monocyte cytotoxicity than those expressing FCGR3A 158F. Together, these results show an association between the FCGR3A 158V allele and risk for HIV-associated CD and suggest that this polymorphism could promote
C. neoformans
pathogenesis via increased binding of
C. neoformans
immune complexes, resulting in increased phagocyte cargo and/or immune activation.

IMPORTANCE
HIV-associated CD4
+
T cell deficiency is a sine qua non for HIV-associated cryptococcal disease (CD), but not all patients with CD4
+
T cell deficiency develop CD despite serological evidence of previous infection. At present, there are no biomarkers that predict HIV-associated CD risk. The goal of our study was to understand whether Fc gamma receptor (FCGR) polymorphisms that have been shown to portend CD risk in HIV-uninfected people are associated with CD risk in HIV-infected people. Such biomarkers could identify those who would benefit most from targeted prophylaxis and/or earlier treatment, particularly in sub-Saharan Africa, where there are nearly a million cases of HIV-associated CD annually. A biomarker of risk could also identify potential candidates for immunization, should there be a vaccine for
Cryptococcus neoformans
.
ON CUSTOMERS ACTING AS SERVERS
Authors: PEREL EFRAT , YECHIALI URI 
Published: August 2013

We consider systems comprised of two interlacing M/M/ • /• type queues, where customers of each queue are the servers of the other queue. Such systems can be found for example in file sharing programs, SETI@home project, and other applications [Arazi, A, E Ben-Jacob and U Yechiali (2005). Controlling an oscillating Jackson-type network having state-dependant service rates. Mathematical Methods of Operations Research, 62, 453–466]. Denoting by Li the number of customers in queue i(Qi), i = 1, 2, we assume that Q1 is a multi-server finite-buffer system with an overall capacity of size N, where the customers there are served by the L2 customers present in Q2. Regarding Q2, we study two different scenarios described as follows: (i) All customers present in Q1 join hands together to form a single server for the customers in Q2, with service time exponentially distributed with an overall intensity μ2L1. That is, the service rate of the customers in Q2 changes dynamically, following the state of Q1. (ii) Each of the customers present in Q1individually acts as a server for the customers in Q2, with service time exponentially distributed with mean 1/μ2. In other words, the number of servers at Q2 changes according to the queue size fluctuations of Q1. We present a probabilistic analysis of such systems, applying both Matrix Geometric method and Probability Generating Functions (PGFs) approach, and derive the stability condition for each model, along with its two-dimensional stationary distribution function. We reveal a relationship between the roots of a given matrix, related to the PGFs, and the stability condition of the systems. In addition, we calculate the means of Li, i = 1, 2, along with their correlation coefficient, and obtain the probability of blocking at Q1. Finally, we present numerical examples and compare between the two models.
CIP2A Modulates Cell-Cycle Progression in Human Cancer Cells by Regulating the Stability and Activity of Plk1
Authors: Kim Jae-Sung , Kim Eun Ju , Oh Jeong Su , Park In-Chul , Hwang Sang-Gu 
Published: August 2013

Abstract
Abnormal cell-cycle control can lead to aberrant cell proliferation and cancer. The oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) is an inhibitor of protein phosphatase 2A (PP2A) that stabilizes c-Myc. However, the precise role of CIP2A in cell division is not understood. Herein, we show that CIP2A is required for mitotic progression by regulating the polo-like kinase (Plk1). With mitotic entry, CIP2A translocated from the cytoplasm to the nucleus, where it was enriched at spindle poles. CIP2A depletion delayed mitotic progression, resulting in mitotic abnormalities independent of PP2A activity. Unexpectedly, CIP2A interacted directly with the polo-box domain of Plk1 during mitosis. This interaction was required to maintain Plk1 stability by blocking APC/C-Cdh1–dependent proteolysis, thereby enhancing the kinase activity of Plk1 during mitosis. We observed strong correlation and in vivo interactions between these two proteins in multiple human cancer specimens. Overall, our results established a novel function for CIP2A in facilitating the stability and activity of the pivotal mitotic kinase Plk1 in cell-cycle progression and tumor development. Cancer Res; 73(22); 6667–78. ©2013 AACR.
Genetic Predictors of Circulating 25-Hydroxyvitamin D and Risk of Colorectal Cancer
Authors: Hiraki Linda T. , Qu Conghui , Hutter Carolyn M. , Baron John A. , Berndt Sonja I. , Bézieau Stéphane , Brenner Hermann , Caan Bette J. , Casey Graham , Chang-Claude Jenny , Chanock Stephen J. , Conti David V. , Duggan David , Fuchs Charles S. , Gallinger Steven , Giovannucci Edward L. , Harrison Tabitha A. , Hayes Richard B. , Hazra Aditi , Henderson Brian , Hoffmeister Michael , Hopper John L. , Hudson Thomas J. , Jenkins Mark A. , Küry Sébastien , Le Marchand Loic , Lemire Mathieu , Ma Jing , Manson JoAnn E. , Nan Hongmei , Newcomb Polly A. , Ng Kimmie , Potter John D. , Schoen Robert E. , Schumacher Fredrick R. , Seminara Daniela , Slattery Martha L. , Wactawski-Wende Jean , White Emily , Wu Kana , Zanke Brent W. , Kraft Peter , Peters Ulrike , Chan Andrew T. 
Published: August 2013

AbstractBackground: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D.Methods: We investigated whether five polymorphisms in GC, CYP2R1, CYP24A1, and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with colorectal cancer risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We conducted a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS).Results: We did not observe a statistically significant association between the 25(OH)D-associated SNPs and colorectal cancer marginally, conditionally, or as a GRS, or for colon or rectal cancer separately.Conclusions: Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of colorectal cancer. Additional work is warranted to investigate the complex relationship between 25(OH)D and colorectal cancer risk.Impact: There was no association observed between genetic markers of circulating 25(OH)D and colorectal cancer. These genetic markers account for a small proportion of the variance in 25(OH)D. Cancer Epidemiol Biomarkers Prev; 22(11); 2037–46. ©2013 AACR.
Temporal Stability of Serum Concentrations of Cytokines and Soluble Receptors Measured Across Two Years in Low-Risk HIV-Seronegative Men
Authors: Epstein Mara M. , Breen Elizabeth Crabb , Magpantay Larry , Detels Roger , Lepone Lauren , Penugonda Sudhir , Bream Jay H. , Jacobson Lisa Paula , Martínez-Maza Otoniel , Birmann Brenda M. 
Published: August 2013

AbstractBackground: Prospective cohort studies often quantify serum immune biomarkers at a single time point to determine risk of cancer and other chronic diseases that develop years later. Estimates of the within-person temporal stability of serum markers partly assess the utility of single biomarker measurements and may have important implications for the design of prospective studies of chronic disease risk.Methods: Using archived sera collected from 200 HIV-seronegative men at three visits spaced over approximately 2 years, concentrations of 14 biomarkers (ApoA1, sCD14, sgp130, sIL-6R, sIL-2Rα, sTNFR2, BAFF/BLyS, CXCL13, IFN-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, and TNF-α) were measured in a single laboratory. Age- and ethnicity-adjusted intraclass correlation coefficients (ICC) were calculated for each biomarker, and mixed linear regression models were used to examine the influence of age, ethnicity, season, and study site on biomarker concentrations.Results: Across all three study visits, most biomarkers had ICC values indicating fair to excellent within-person stability. ApoA1 (ICC = 0.88) and TNF-α (ICC = 0.87) showed the greatest stability; the ICC for IL-8 (ICC = 0.33) was remarkably less stable. The ICCs were similar when calculated between pairs of consecutive visits. The covariables did not influence biomarker levels or their temporal stability. All biomarkers showed moderate to strong pairwise correlations across visits.Conclusions: Serum concentrations of most evaluated immune biomarkers displayed acceptable to excellent within-person temporal reliability over a 2-year period. Further investigation may be required to clarify the stability of IL-8.Impact: These findings lend support to using these serologic immune biomarkers in prospective studies investigating associations with chronic diseases. Cancer Epidemiol Biomarkers Prev; 22(11); 2009–15. ©2013 AACR.