bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time‐of‐day variation in vascular function
Authors: Rodrigo G. C. , Denniff M. 
Published: October 2016

New Findings

What is the topic of this review?
This report looks at the role of endothelial nitric oxide signalling in the time‐of‐day variation in vasoconstriction of resistance vessels.

What advances does it highlight?
It highlights a time‐of‐day variation in contraction of mesenteric arteries, characterized by a reduced contractile response to either phenylephrine or high K+ and increased relaxation in response to acetylcholine during the active period. This time‐of‐day variation in contraction results from a difference in endothelial nitric oxide synthase (eNOS) signalling that correlates with levels of eNOS expression, which peak during the active period and may have far reaching physiological consequences beyond regulation of blood pressure.

There is a strong time‐of‐day variation in the vasoconstriction in response to sympathetic stimulation that may contribute to the time‐of‐day variation in blood pressure, which is characterized by a dip in blood pressure during the individual's rest period when sympathetic activity is low. Vasoconstriction is known to be regulated tightly by nitric oxide signalling from the endothelial cells, so we have looked at the effect of time‐of‐day on levels of endothelial nitric oxide synthase (eNOS) and vascular contractility. Mesenteric arteries isolated from the nocturnal rat exhibit a time‐of‐day variation in their contractile response to α1‐adrenoreceptor and muscarinic activation, which is characterized by a reduced vasoconstriction in response to phenylephrine and enhanced vasodilatation in response to acetylcholine during the rat's active period at night. An increase in eNOS signalling during the active period is responsible for this time‐of‐day difference in response to phenylephrine and acetylcholine and correlates with the large increase in eNOS expression (mRNA and protein) during the active period, possibly driven by the presence of a functioning peripheral circadian clock. This increase in eNOS signalling may function to limit the increase in peripheral resistance and therefore blood pressure during the increased sympathetic activity.
Pleiotropic function of TRPV4 ion channels in the central nervous system
Authors: Kanju Patrick , Liedtke Wolfgang 
Published: October 2016

New Findings
What is the topic of this review?
In this concise review, we highlight insights into the role of transient receptor potential, vanilloid type 4 (TRPV4) ion channels in the CNS, results that have been contributed over the last 16 years since the initial discovery of the channel.

What advances does it highlight?
TRPV4 has been found to function in neurons, astroglia and microglia, both in physiological (e.g. astrocytic neurovascular coupling, neuronal membrane potential at physiological temperature) and in pathological conditions (e.g. mechanical trauma), so far recorded as exciting findings in need of more in‐depth mechanistic clarification.

Transient receptor potential, vanilloid type 4 (TRPV4) ion channels are osmo‐mechano‐TRP channels, with pleiotropic function and expression in many different types of tissues and cells. They have also been found to be involved in pain and inflammation. Studies have focused on the role of TRPV4 in peripheral sensory neurons, but its expression and function in central nervous glial cells and neurons has also been documented. In this overview, based on the senior author’s (WL) lecture at the recent recent joint meeting of APS/The Physiological Society in Dublin, we concisely review evidence of TRPV4 expression and function in the CNS and how TRPV4 function can be modulated for therapeutic benefit of neuropsychiatric disorders. Novel TRPV4‐inhibitory compounds developed recently in the authors’ laboratory are also discussed.
The effects of cold water immersion and active recovery on inflammation and cell stress responses in human skeletal muscle after resistance exercise
Authors: Peake Jonathan M. , Roberts Llion A. , Figueiredo Vandre C. , Egner Ingrid , Krog Simone , Aas Sigve N. , Suzuki Katsuhiko , Markworth James F. , Coombes Jeff S. , Cameron‐Smith David , Raastad Truls 
Published: October 2016

Key points
Cold water immersion and active recovery are common post‐exercise recovery treatments. A key assumption about the benefits of cold water immersion is that it reduces inflammation in skeletal muscle. However, no data are available from humans to support this notion.
We compared the effects of cold water immersion and active recovery on inflammatory and cellular stress responses in skeletal muscle from exercise‐trained men 2, 24 and 48 h during recovery after acute resistance exercise.
Exercise led to the infiltration of inflammatory cells, with increased mRNA expression of pro‐inflammatory cytokines and neurotrophins, and the subcellular translocation of heat shock proteins in muscle. These responses did not differ significantly between cold water immersion and active recovery.
Our results suggest that cold water immersion is no more effective than active recovery for minimizing the inflammatory and stress responses in muscle after resistance exercise.
AbstractCold water immersion and active recovery are common post‐exercise recovery treatments. However, little is known about whether these treatments influence inflammation and cellular stress in human skeletal muscle after exercise. We compared the effects of cold water immersion versus active recovery on inflammatory cells, pro‐inflammatory cytokines, neurotrophins and heat shock proteins (HSPs) in skeletal muscle after intense resistance exercise. Nine active men performed unilateral lower‐body resistance exercise on separate days, at least 1 week apart. On one day, they immersed their lower body in cold water (10°C) for 10 min after exercise. On the other day, they cycled at a low intensity for 10 min after exercise. Muscle biopsies were collected from the exercised leg before, 2, 24 and 48 h after exercise in both trials. Exercise increased intramuscular neutrophil and macrophage counts, MAC1 and CD163 mRNA expression (P < 0.05). Exercise also increased IL1β, TNF, IL6, CCL2, CCL4, CXCL2, IL8 and LIF mRNA expression (P < 0.05). As evidence of hyperalgesia, the expression of NGF and GDNF mRNA increased after exercise (P < 0.05). The cytosolic protein content of αB‐crystallin and HSP70 decreased after exercise (P < 0.05). This response was accompanied by increases in the cytoskeletal protein content of αB‐crystallin and the percentage of type II fibres stained for αB‐crystallin. Changes in inflammatory cells, cytokines, neurotrophins and HSPs did not differ significantly between the recovery treatments. These findings indicate that cold water immersion is no more effective than active recovery for reducing inflammation or cellular stress in muscle after a bout of resistance exercise.
Genetic Dissection of the Type VI Secretion System in
Acinetobacter
and Identification of a Novel Peptidoglycan Hydrolase, TagX, Required for Its Biogenesis
Authors: Weber Brent S. , Hennon Seth W. , Wright Meredith S. , Scott Nichollas E. , de Berardinis Véronique , Foster Leonard J. , Ayala Juan A. , Adams Mark D. , Feldman Mario F. 
Published: October 2016

ABSTRACT

The type VI secretion system (T6SS) is a widespread secretory apparatus produced by Gram-negative bacteria that has emerged as a potent mediator of antibacterial activity during interbacterial interactions. Most
Acinetobacter
species produce a genetically conserved T6SS, although the expression and functionality of this system vary among different strains. Some pathogenic
Acinetobacter baumannii
strains activate this secretion system via the spontaneous loss of a plasmid carrying T6SS repressors. In this work, we compared the expression of T6SS-related genes via transcriptome sequencing and differential proteomics in cells with and without the plasmid. This approach, together with the mutational analysis of the T6SS clusters, led to the determination of the genetic components required to elaborate a functional T6SS in the nosocomial pathogen
A. baumannii
and the nonpathogen
A. baylyi
. By constructing a comprehensive combination of mutants with changes in the T6SS-associated
vgrG
genes, we delineated their relative contributions to T6SS function. We further determined the importance of two effectors, including an effector-immunity pair, for antibacterial activity. Our genetic analysis led to the identification of an essential membrane-associated structural component named TagX, which we have characterized as a peptidoglycan hydrolase possessing
l
,
d
-endopeptidase activity. TagX shows homology to known bacteriophage
l
,
d
-endopeptidases and is conserved in the T6SS clusters of several bacterial species. We propose that TagX is the first identified enzyme that fulfills the important role of enabling the transit of T6SS machinery across the peptidoglycan layer of the T6SS-producing bacterium.

IMPORTANCE
Acinetobacter baumannii
is one of the most troublesome and least investigated multidrug-resistant bacterial pathogens. We have previously shown that
A. baumannii
employs a T6SS to eliminate competing bacteria. Here we provide a comprehensive analysis of the components of the T6SS of
Acinetobacter
, and our results provide genetic and functional insights into the
Acinetobacter
T6SS. Through this analysis, we identified a novel peptidoglycan hydrolase, TagX, that is required for biogenesis of the T6SS apparatus. This is the first peptidoglycanase specialized in T6SS function identified in any species. We propose that this enzyme is required for the spatially and temporally regulated digestion of peptidoglycan to allow assembly of the T6SS machinery.
No-Go Zones for Mariner Transposition
Authors: Akerley Brian J. 
Published: October 2016

ABSTRACT

The property of transposons to randomly insert into target DNA has long been exploited for generalized mutagenesis and forward genetic screens. Newer applications that monitor the relative abundance of each transposon insertion in large libraries of mutants can be used to evaluate the roles in cellular fitness of all genes of an organism, provided that transposition is in fact random across all genes. In a recent article, Kimura and colleagues identified an important exception to the latter assumption [S. Kimura, T. P. Hubbard, B. M. Davis, M. K. Waldor, mBio 7(4):e01351-16, 2016, doi:10.1128/mBio.01351-16]. They provide evidence that the Mariner transposon exhibits locus-specific site preferences in the presence of the histone-like nucleoid structuring protein H-NS. This effect was shown to bias results for important virulence loci in
Vibrio cholerae
and to result in misidentification of genes involved in growth
in vitro
. Fortunately, the bulk of this bacterium’s genome was unaffected by this bias, and recognizing the H-NS effect allows filtering to improve the accuracy of the results.
Respiratory distress syndrome in moderately late and late preterm infants and risk of cerebral palsy: a population-based cohort study
Authors: Thygesen Sandra Kruchov , Olsen Morten , Østergaard John R , Sørensen Henrik Toft 
Published: October 2016

ObjectivesInfant respiratory distress syndrome (IRDS) is a known risk factor for intracerebral haemorrhage/intraventricular haemorrhage (ICH/IVH) and periventricular leucomalacia. These lesions are known to increase the risk of cerebral palsy (CP). Thus, we wanted to examine the long-term risk of CP following IRDS in moderately late and late preterm infants.DesignPopulation-based cohort study.SettingAll hospitals in Denmark.ParticipantsWe used nationwide medical registries to identify a cohort of all moderately and late preterm infants (defined as birth during 32–36 full gestational weeks) born in Denmark in 1997–2007 with and without hospital diagnosed IRDS.Main outcomes measuresWe followed study participants from birth until first diagnosis of CP, emigration, death or end of follow-up in 2014. We computed the cumulative incidence of CP before age 8 years and used Cox's regression analysis to compute HRs of IRDS, comparing children with IRDS to those without IRDS. HRs were adjusted for multiple covariates.ResultsWe identified 39 420 moderately late and late preterm infants, of whom 2255 (5.7%) had IRDS. The cumulative incidence of CP was 1.9% in infants with IRDS and 0.5% in the comparison cohort. The adjusted HR of CP was 2.0 (95% CI 1.4 to 2.9). The adjusted HR of CP was 12 (95% CI 4.5 to 34) in children with IRDS accompanied by a diagnosis of ICH/IVH. After restriction to children without diagnoses of perinatal breathing disorders other than IRDS, congenital heart disease and viral or bacterial infections occurring within 4 days of birth, the overall adjusted HR was 2.1 (95% CI 1.4 to 3.1).ConclusionsThe risk of CP was increased in moderately late and late preterm infants with IRDS compared with infants without IRDS born during the same gestational weeks.
Development of guidance on the timeliness in response to acute kidney injury warning stage test results for adults in primary care: an appropriateness ratings evaluation
Authors: Blakeman Tom , Griffith Kathryn , Lasserson Dan , Lopez Berenice , Tsang Jung Y , Campbell Stephen , Tomson Charles 
Published: October 2016

ObjectivesTackling the harm associated with acute kidney injury (AKI) is a global priority. In England, a national computerised AKI algorithm is being introduced across the National Health Service (NHS) to drive this change. The study sought to maximise its clinical utility and minimise the potential for burden on clinicians and patients in primary care.DesignAn appropriateness ratings evaluation using the RAND/UCLA Appropriateness Method.SettingClinical scenarios were developed to test the timeliness in (1) communication of AKI warning stage test results from clinical pathology services to primary care, and (2) primary care clinician response to an AKI warning stage test result.ParticipantsA 10-person panel was purposively sampled with representation from clinical biochemistry, acute and emergency medicine and general practice. General practitioners (GPs) represented typical practice in relation to rural and urban practice, out of hours care, GP commissioning and those interested in reducing the impact of medicalisation and ‘overdiagnosis’.ResultsThere was agreement that delivery of AKI warning stage test results through interruptive methods of communication (ie, telephone) from laboratories to primary care was the appropriate next step for patients with an AKI warning stage 3 test result. In the context of acute illness, waiting up to 72 hours to respond to an AKI warning stage test result was deemed an inappropriate action in 62 out of the 65 (94.5%) cases. There was agreement that a clinician response was required within 6 hours, or less, in 39 out of 40 (97.5%) clinical cases relating AKI warning stage test results in the presence of moderate hyperkalaemia.ConclusionsThe study has informed national guidance to support a timely and calibrated response to AKI warning stage test results for adults in primary care. Further research is needed to support effective implementation, with a view to examine the effect on health outcomes and costs.
Continuous measurement of breast tumour hormone receptor expression: a comparison of two computational pathology platforms
Authors: Ahern Thomas P , Beck Andrew H , Rosner Bernard A , Glass Ben , Frieling Gretchen , Collins Laura C , Tamimi Rulla M 
Published: October 2016

AimsComputational pathology platforms incorporate digital microscopy with sophisticated image analysis to permit rapid, continuous measurement of protein expression. We compared two computational pathology platforms on their measurement of breast tumour oestrogen receptor (ER) and progesterone receptor (PR) expression.MethodsBreast tumour microarrays from the Nurses' Health Study were stained for ER (n=592) and PR (n=187). One expert pathologist scored cases as positive if ≥1% of tumour nuclei exhibited stain. ER and PR were then measured with the Definiens Tissue Studio (automated) and Aperio Digital Pathology (user-supervised) platforms. Platform-specific measurements were compared using boxplots, scatter plots and correlation statistics. Classification of ER and PR positivity by platform-specific measurements was evaluated with areas under receiver operating characteristic curves (AUC) from univariable logistic regression models, using expert pathologist classification as the standard.ResultsBoth platforms showed considerable overlap in continuous measurements of ER and PR between positive and negative groups classified by expert pathologist. Platform-specific measurements were strongly and positively correlated with one another (r≥0.77). The user-supervised Aperio workflow performed slightly better than the automated Definiens workflow at classifying ER positivity (AUCAperio=0.97; AUCDefiniens=0.90; difference=0.07, 95% CI 0.05 to 0.09) and PR positivity (AUCAperio=0.94; AUCDefiniens=0.87; difference=0.07, 95% CI 0.03 to 0.12).ConclusionsPaired hormone receptor expression measurements from two different computational pathology platforms agreed well with one another. The user-supervised workflow yielded better classification accuracy than the automated workflow. Appropriately validated computational pathology algorithms enrich molecular epidemiology studies with continuous protein expression data and may accelerate tumour biomarker discovery.
SRVM
Authors: Xu Xin , Davda Bhavesh 
Published: October 2016

Single-Root I/O Virtualization (SR-IOV) is a specification that allows a single PCI Express (PCIe) device (ysical function or PF) to be used as multiple PCIe devices (virtual functions or VF). In a virtualization system, each VF can be directly assigned to a virtual machine (VM) in passthrough mode to significantly improve the network performance. However, VF passthrough mode is not compatible with live migration, which is an essential capability that enables many advanced virtualization features such as high availability and resource provisioning.
To solve this problem, we design SRVM which provides hypervisor support to ensure the VF device can be correctly used by the migrated VM and the applications. SRVM is implemented in the hypervisor without modification in guest operating systems or guest VM drivers. Our experimental results show that SRVM can effectively migrate all memory state, and there is no data loss or corruption in applications after live migration. SRVM does not increase VM downtime. It only costs limited resources (an extra CPU core), and there is no significant runtime overhead in VM network performance. In fact, since the VF can continue to be used during the pre-copy ase, it offers network throughput which is 9.6 times and network latency which is 98% lower compared to other solutions that switch to para-virtualization mode during live migration.
Performance Implications of Extended Page Tables on Virtualized x86 Processors
Authors: Merrifield Timothy , Taheri H. Reza 
Published: October 2016

Managing virtual memory is an expensive operation, and becomes even more expensive on virtualized servers. Process- ing TLB misses on a virtualized x86 server requires a two-dimensional page walk that can have 6x more page table lookups, hence 6x more memory references, than a native page table walk. Thus much of the recent research on the subject starts from the assumption that TLB miss processing in virtual environments is significantly more expensive than on native servers. However, we will show that with the latest software stack on modern x86 processors, most of these page-table lookups are satisfied by internal paging structure caches and the L1/L2 data caches, and the actual virtualization overhead of TLB miss processing is a modest fraction of the overall time spent processing TLB misses.
In this paper, we present a detailed accounting of the TLB miss processing costs on virtualized x86 servers for an exhaustive set of workloads, in particular, two very demanding industry standard workloads. We show that an implementation of the TPC-C workload that actively uses 475 GB of memory on a 72-CPU Haswell-EP server spends 20% of its time processing TLB misses when the application runs in a VM. Although this is a non-trivial amount, it is only 4.2% higher than the TLB miss processing costs on bare metal. The multi-VM VMmark benchmark sees 12.3% in TLB miss processing, but only 4.3% of that can be attributed to virtualization overheads. We show that even for the heaviest workloads, a well-tuned application that uses large pages on a recent OS release with a modern hypervisor running on the latest x86 processors sees only minimal degradation from the additional overhead of the two-dimensional page walks in a virtualized server.
Clarithromycin increases neuronal excitability in CA3 pyramidal neurons through a reduction in GABAergic signaling
Authors: Bichler Edyta K. , Elder Courtney C. , García Paul S. 
Published: October 2016

Antibiotics are used in the treatment and prevention of bacterial infections, but effects on neuron excitability have been documented. A recent study demonstrated that clarithromycin alleviates daytime sleepiness in hypersomnia patients (Trotti LM, Saini P, Freeman AA, Bliwise DL, García PS, Jenkins A, Rye DB. J Psychopharmacol 28: 697–702, 2014). To explore the potential application of clarithromycin as a stimulant, we performed whole cell patch-clamp recordings in rat pyramidal cells from the CA3 region of hippocampus. In the presence of the antibiotic, rheobase current was reduced by 50%, F-I relationship (number of action potentials as a function of injected current) was shifted to the left, and the resting membrane potential was more depolarized. Clarithromycin-induced hyperexcitability was dose dependent; doses of 30 and 300 μM clarithromycin significantly increased the firing frequency and membrane potential compared with controls ( P = 0.003, P < 0.0001). We hypothesized that clarithromycin enhanced excitability by reducing GABAA receptor activation. Clarithromycin at 30 μM significantly reduced ( P = 0.001) the amplitude of spontaneous miniature inhibitory GABAergic currents and at 300 μM had a minor effect on action potential width. Additionally, we tested the effect of clarithromycin in an ex vivo seizure model by evaluating its effect on spontaneous local field potentials. Bath application of 300 μM clarithromycin enhanced burst frequency twofold compared with controls ( P = 0.0006). Taken together, these results suggest that blocking GABAergic signaling with clarithromycin increases cellular excitability and potentially serves as a stimulant, facilitating emergence from anesthesia or normalizing vigilance in hypersomnia and narcolepsy. However, the administration of clarithromycin should be carefully considered in patients with seizure disorders. NEW & NOTEWORTHY Clinical administration of the macrolide antibiotic clarithromycin has been associated with side effects such as mania, agitation, and delirium. Here, we investigated the adverse effects of this antibiotic on CA3 pyramidal cell excitability. Clarithromycin induces hyperexcitability in single neurons and is related to a reduction in GABAergic signaling. Our results support a potentially new application of clarithromycin as a stimulant to facilitate emergence from anesthesia or to normalize vigilance.