bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deficiency of GABAergic synaptic inhibition in the Kölliker–Fuse area underlies respiratory dysrhythmia in a mouse model of Rett syndrome
Authors: Abdala Ana Paula , Toward Marie A. , Dutschmann Mathias , Bissonnette John M. , Paton Julian F. R. 
Published: October 2015

Key points
Life threatening breathing irregularity and central apnoeas are highly prevalent in children suffering from Rett syndrome.
Abnormalities in inhibitory synaptic transmission have been associated with the physiopathology of this syndrome, and may underlie the respiratory disorder.
In a mouse model of Rett syndrome, GABAergic terminal projections are markedly reduced in the Kölliker–Fuse nucleus (KF) in the dorsolateral pons, an important centre for control of respiratory rhythm regularity.
Administration of a drug that augments endogenous GABA localized to this region of the pons reduced the incidence of apnoea and the respiratory irregularity of Rett female mice. Conversely, the respiratory disorder was recapitulated by blocking GABAergic transmission in the KF area of healthy rats.
This study helps us understand the mechanism for generation of respiratory abnormality in Rett syndrome, pinpoints a brain site responsible and provides a clear anatomical target for the development of a translatable drug treatment.
AbstractCentral apnoeas and respiratory irregularity are a common feature in Rett syndrome (RTT), a neurodevelopmental disorder most often caused by mutations in the methyl‐CpG‐binding protein 2 gene (MECP2). We used a MECP2 deficient mouse model of RTT as a strategy to obtain insights into the neurobiology of the disease and into mechanisms essential for respiratory rhythmicity during normal breathing. Previously, we showed that, systemic administration of a GABA reuptake blocker in MECP2 deficient mice markedly reduced the occurrence of central apnoeas. Further, we found that, during central apnoeas, post‐inspiratory drive (adductor motor) to the upper airways was enhanced in amplitude and duration in Mecp2 heterozygous female mice. Since the pontine Kölliker–Fuse area (KF) drives post‐inspiration, suppresses inspiration, and can reset the respiratory oscillator phase, we hypothesized that synaptic inhibition in this area is essential for respiratory rhythm regularity. In this study, we found that: (i) Mecp2 heterozygous mice showed deficiency of GABA perisomatic bouton‐like puncta and processes in the KF nucleus; (ii) blockade of GABA reuptake in the KF of RTT mice reduced breathing irregularity; (iii) conversely, blockade of GABAA receptors in the KF of healthy rats mimicked the RTT respiratory phenotype of recurrent central apnoeas and prolonged post‐inspiratory activity. Our results show that reductions in synaptic inhibition within the KF induce rhythm irregularity whereas boosting GABA transmission reduces respiratory arrhythmia in a murine model of RTT. Our data suggest that manipulation of synaptic inhibition in KF may be a clinically important strategy for alleviating the life threatening respiratory disorders in RTT.
Respiratory modulated sympathetic activity: a putative mechanism for developing vascular resistance?
Authors: Briant Linford J. B. , O'Callaghan Erin L. , Champneys Alan R. , Paton Julian F. R. 
Published: October 2015

Key points
Sympathetic activity exhibits respiratory modulation that is amplified in hypertensive rats.
Respiratory modulated sympathetic activity produces greater changes in vascular resistance than tonic stimulation of the same stimulus magnitude in normotensive but not hypertensive rats.
Mathematical modelling demonstrates that respiratory modulated sympathetic activity may fail to produce greater vascular resistance changes in hypertensive rats because the system is saturated as a consequence of a dysfunctional noradrenaline reuptake mechanism.
Respiratory modulated sympathetic activity is an efficient mechanism to raise vascular resistance promptly, corroborating its involvement in the ontogenesis of hypertension.
AbstractSympathetic nerve activity (SNA) exhibits respiratory modulation. This component of SNA is important – being recruited under cardiorespiratory reflex conditions and elevated in the spontaneously hypertensive (SH) rat – and yet the exact influence of this modulation on vascular tone is not understood, even in normotensive conditions. We constructed a mathematical model of the sympathetic innervation of an arteriole, and used it to test the hypothesis that respiratory modulation of SNA preferentially increases vasoconstriction compared to a frequency‐matched tonic pattern. Simulations supported the hypothesis, where respiratory modulated increases in vasoconstriction were mediated by a noradrenergic mechanism. These predictions were tested in vivo in adult Wistar rats. Stimulation of the sympathetic chain (L3) with respiratory modulated bursting patterns, revealed that bursting increases vascular resistance (VR) more than tonic stimulation (57.8 ± 3.3% vs. 44.8 ± 4.2%; P < 0.001; n = 8). The onset of the VR response was also quicker for bursting stimulation (rise time constant = 1.98 ± 0.09 s vs. 2.35 ± 0.20 s; P < 0.01). In adult SH rats (n = 8), the VR response to bursting (44.6 ± 3.9%) was not different to tonic (37.4 ± 3.5%; P = 0.57). Using both mathematical modelling and in vivo techniques, we have shown that VR depends critically on respiratory modulation and revealed that this pattern dependency in Wistar rats is due to a noradrenergic mechanism. This respiratory component may therefore contribute to the ontogenesis of hypertension in the pre‐hypertensive SH rat – raising VR and driving vascular remodelling. Why adult SH rats do not exhibit a pattern‐dependent response is not known, but further modelling revealed that this may be due to dysfunctional noradrenaline reuptake.
Dendritic Cell Autophagy Contributes to Herpes Simplex Virus-Driven Stromal Keratitis and Immunopathology
Authors: Jiang Yike , Yin Xiaotang , Stuart Patrick M. , Leib David A. 
Published: October 2015

ABSTRACTHerpetic stromal keratitis (HSK) is a blinding ocular disease that is initiated by HSV-1 and characterized by chronic inflammation in the cornea. Although HSK immunopathology of the cornea is well documented in animal models, events preceding this abnormal inflammatory cascade are poorly understood. In this study, we have examined the activation of pathological CD4+T cells in the development of HSK. Dendritic cell autophagy (DC-autophagy) is an important pathway regulating major histocompatibility complex class II (MHCII)-dependent antigen presentation and proper CD4+T cell activation during infectious diseases. Using DC-autophagy-deficient mice, we found that DC-autophagy significantly and specifically contributes to HSK disease without impacting early innate immune infiltration, viral clearance, or host survival. Instead, the observed phenotype was attributable to the abrogated activation of CD4+T cells and reduced inflammation in HSK lesions. We conclude that DC-autophagy is an important contributor to primary HSK immunopathology upstream of CD4+T cell activation.IMPORTANCEHerpetic stromal keratitis (HSK) is the leading cause of infectious blindness in the United States and a rising cause worldwide. HSK is induced by herpes simplex virus 1 but is considered a disease of inappropriately sustained inflammation driven by CD4+T cells. In this study, we investigated whether pathways preceding CD4+T cell activation affect disease outcome. We found that autophagy in dendritic cells significantly contributed to the incidence of HSK. Dendritic cell autophagy did not alter immune control of the virus or neurological disease but specifically augmented CD4+T cell activation and pathological corneal inflammation. This study broadens our understanding of the immunopathology that drives HSK and implicates the autophagy pathway as a new target for therapeutic intervention against this incurable form of infectious blindness.
Toxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous System
Authors: Brooks Justin M. , Carrillo Gabriela L. , Su Jianmin , Lindsay David S. , Fox Michael A. , Blader Ira J. 
Published: October 2015

ABSTRACTDuring infections with the protozoan parasiteToxoplasma gondii, gamma-aminobutyric acid (GABA) is utilized as a carbon source for parasite metabolism and also to facilitate parasite dissemination by stimulating dendritic-cell motility. The best-recognized function for GABA, however, is its role in the nervous system as an inhibitory neurotransmitter that regulates the flow and timing of excitatory neurotransmission. When this pathway is altered, seizures develop. Human toxoplasmosis patients suffer from seizures, suggesting thatToxoplasmainterferes with GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic proteins appeared normal, infection with type II ME49Toxoplasmatissue cysts led to global changes in the distribution of glutamic acid decarboxylase 67 (GAD67), a key enzyme that catalyzes GABA synthesis in the brain. Alterations in GAD67 staining were not due to decreased expression but rather to a change from GAD67 clustering at presynaptic termini to a more diffuse localization throughout the neuropil. Consistent with a loss of GAD67 from the synaptic terminals,Toxoplasma-infected mice develop spontaneous seizures and are more susceptible to drugs that induce seizures by antagonizing GABA receptors. Interestingly, GABAergic protein mislocalization and the response to seizure-inducing drugs were observed in mice infected with type II ME49 but not type III CEP strain parasites, indicating a role for a polymorphic parasite factor(s) in regulating GABAergic synapses. Taken together, these data support a model in which seizures and other neurological complications seen inToxoplasma-infected individuals are due, at least in part, to changes in GABAergic signaling.IMPORTANCEInfections of the central nervous system can cause seizures. While inflammation in the brain has been proposed to initiate the onset of the seizures, relatively little is known about how inflammation impacts the structure and function of the neurons. Here we used a parasite calledToxoplasma gondiithat infects the brain and showed that seizures arise due to a defect in signaling of GABA, which is the neurotransmitter primarily responsible for preventing the onset of seizures.
Intrinsic Antimicrobial Resistance Determinants in the Superbug Pseudomonas aeruginosa
Authors: Murray Justine L. , Kwon Taejoon , Marcotte Edward M. , Whiteley Marvin 
Published: October 2015

ABSTRACTAntimicrobial-resistant bacteria pose a serious threat in the clinic. This is particularly true for opportunistic pathogens that possess high intrinsic resistance. Though many studies have focused on understanding the acquisition of bacterial resistance upon exposure to antimicrobials, the mechanisms controlling intrinsic resistance are not well understood. In this study, we subjected the model opportunistic superbugPseudomonas aeruginosato 14 antimicrobials under highly controlled conditions and assessed its response using expression- and fitness-based genomic approaches. Our results reveal that gene expression changes and mutant fitness in response to sub-MIC antimicrobials do not correlate on a genomewide scale, indicating that gene expression is not a good predictor of fitness determinants. In general, fewer fitness determinants were identified for antiseptics and disinfectants than for antibiotics. Analysis of gene expression and fitness data together allowed the prediction of antagonistic interactions between antimicrobials and insight into the molecular mechanisms controlling these interactions.IMPORTANCEInfections involving multidrug-resistant pathogens are difficult to treat because the therapeutic options are limited. These infections impose a significant financial burden on infected patients and on health care systems. Despite years of antimicrobial resistance research, we lack a comprehensive understanding of the intrinsic mechanisms controlling antimicrobial resistance. This work uses two fine-scale genomic approaches to identify genetic loci important for antimicrobial resistance of the opportunistic pathogenPseudomonas aeruginosa. Our results reveal that antibiotics have more resistance determinants than antiseptics/disinfectants and that gene expression upon exposure to antimicrobials is not a good predictor of these resistance determinants. In addition, we show that when used together, genomewide gene expression and fitness profiling can provide mechanistic insights into multidrug resistance mechanisms.
U–Pb and Lu–Hf zircon data in young sediments reflect sedimentary recycling in eastern South Africa
Authors: Andersen Tom , Elburg Marlina , Cawthorn-Blazeby Anton 
Published: October 2015

Detrital zircon from unconsolidated, Cenozoic sediments from eastern South Africa has been analysed for U–Pb and Lu–Hf isotopes by laser ablation inductively coupled plasma mass spectrometry. Identifiable bedrock sources have made local contributions to the detrital zircon populations, but the dominant zircon components are of regional distribution: late Mesoproterozoic (ε
Hf
= –5 to +10), Neoproterozoic to early Palaeozoic (ε
Hf
= –10 to +10), and minor late Palaeozoic (ε
Hf
≈ 0). Archaean zircons are scarce even in sediments deposited on exposed Archaean basement or by rivers eroding it. The dominant components cannot be tied to specific first-generation sources in southern Africa or its former Gondwana neighbours. Instead, we see the effect of mixing and remobilization of debris from large parts of the supercontinent in the early Phanerozoic, which was stored in the Karoo basin and other continental cover sequences and shed from there to the present site of deposition. Therefore, data from detrital zircon in these deposits tell us less about the path of detritus from source to sink in a recent sedimentary system than about processes in much earlier erosion–transport–deposition cycles. To facilitate comparison of detrital zircon age distribution patterns, a simple and intuitive method that takes sampling uncertainty explicitly into account is proposed.

Supplementary materials:

U–Pb and Lu–Hf data, and concordia diagrams and discussion of effects of discordance are available at
http://www.geolsoc.org.uk/SUP18884
.
The Natural History Museum Fossil Fish Collection: Smith Woodward’s role in the development and use of this priceless resource
Authors: Smith Mike 
Published: October 2015

Abstract

When an 18-year-old Arthur Smith Woodward arrived at the new home of the natural history collections of the British Museum on Cromwell Road, South Kensington in August 1882, he could not have envisaged the treasure trove of vertebrate fossils that awaited him. Even before the move to South Kensington, the collections already contained many fossil fish specimens first described and figured by the famous Swiss zoologist and geologist Louis Agassiz in his monumental work
Recherches sur les Poissons Fossiles
. The fabulous fossil fish collections of Lord Egerton and the Earl of Enniskillen arrived shortly after, including many more of Agassiz's type specimens. However, Agassiz had left much work undone and ideas on fossil fish systematics had changed in the 50 years since he had started publishing his research. Making full use of the collection, and adding to it, Smith Woodward embarked on a scientific career that was to see him become the world's leading authority on fossil fishes. When he retired from the Museum at the age of 60, his successors inherited the most extensive and well-documented collection of fossil fishes in the world.
Tumor Cell-Derived Periostin Regulates Cytokines That Maintain Breast Cancer Stem Cells
Authors: Lambert Arthur W. , Wong Chen Khuan , Ozturk Sait , Papageorgis Panagiotis , Raghunathan Rekha , Alekseyev Yuriy , Gower Adam C. , Reinhard Björn M. , Abdolmaleky Hamid M. , Thiagalingam Sam 
Published: October 2015

Abstract
Basal-like breast cancer (BLBC) is an aggressive subtype of breast cancer which is often enriched with cancer stem cells (CSC), but the underlying molecular basis for this connection remains elusive. We hypothesized that BLBC cells are able to establish a niche permissive to the maintenance of CSCs and found that tumor cell-derived periostin (POSTN), a component of the extracellular matrix, as well as a corresponding cognate receptor, integrin αvβ3, are highly expressed in a subset of BLBC cell lines as well as in CSC-enriched populations. Furthermore, we demonstrated that an intact periostin–integrin β3 signaling axis is required for the maintenance of breast CSCs. POSTN activates the ERK signaling pathway and regulates NF-κB–mediated transcription of key cytokines, namely IL6 and IL8, which in turn control downstream activation of STAT3. In summary, these findings suggest that BLBC cells have an innate ability to establish a microenvironmental niche supportive of CSCs.
Implications: The findings reported here indicate that POSTN produced by CSCs acts to reinforce the stem cell state through the activation of integrin receptors and the production of key cytokines. Mol Cancer Res; 14(1); 103–13. ©2015 AACR.
Reducing the Blood Pressure–Related Burden of Cardiovascular Disease: Impact of Achievable Improvements in Blood Pressure Prevention and Control
Authors: Hardy Shakia T. , Loehr Laura R. , Butler Kenneth R. , Chakladar Sujatro , Chang Patricia P. , Folsom Aaron R. , Heiss Gerardo , MacLehose Richard F. , Matsushita Kunihiro , Avery Christy L. 
Published: October 2015

Background

US
blood pressure reduction policies are largely restricted to hypertensive populations and associated benefits are often estimated based on unrealistic interventions.

Methods and Results

We used multivariable linear regression to estimate incidence rate differences contrasting the impact of 2 pragmatic hypothetical interventions to reduce coronary heart disease, stroke, and heart failure (
HF
) incidence: (1) a population‐wide intervention that reduced systolic blood pressure by 1 mm Hg and (2) targeted interventions that reduced the prevalence of unaware, untreated, or uncontrolled blood pressure above goal (per Eighth Joint National Committee treatment thresholds) by 10%. In the Atherosclerosis Risk in Communities Study (n=15 744; 45 to 64 years at baseline, 1987–1989), incident coronary heart disease and stroke were adjudicated by physician panels. Incident
HF
was defined as the first hospitalization with discharge diagnosis code of “428.” A 10% proportional reduction in unaware, untreated, or uncontrolled blood pressure above goal resulted in ≈4.61, 3.55, and 11.01 fewer
HF
events per 100 000 person‐years in African Americans, and 3.77, 1.63, and 4.44 fewer
HF
events per 100 000 person‐years, respectively, in whites. In contrast, a 1 mm Hg population‐wide systolic blood pressure reduction was associated with 20.3 and 13.3 fewer
HF
events per 100 000 person‐years in African Americans and whites, respectively. Estimated event reductions for coronary heart disease and stroke were smaller than for
HF
, but followed a similar pattern for both population‐wide and targeted interventions.

Conclusions
Modest population‐wide shifts in systolic blood pressure could have a substantial impact on cardiovascular disease incidence and should be developed in parallel with interventions targeting populations with blood pressure above goal.
Unions and the organising turn: Reflections after 20 years of Organising Works
Authors: Heery Edmund 
Published: October 2015

AbstractThe launch of Organising Works 20 years ago was a key event, not just in the history of Australian trade unions but on a global scale. It marked the beginning of what might be termed the ‘organising turn’, a shift across the international trade union movement towards the greater prioritisation of union organising. This article reviews the 20-year experience of the turn, reflecting upon three of its core attributes. The first is the origin of much activity at the apex of the official trade union movement and the consequences that flow from this point of origin. The second is the emphasis on diversity, with a particular priority in recent times in trying to organise low-wage migrant workers in precarious employment. The final attribute can be labelled ‘neo-syndicalism’. This term refers to a switch towards the ‘internal’ renewal of trade unions and in this regard can be counterposed to attempts at revitalisation that focus on rebuilding relations with government and employers. The article concludes by arguing that organising can and must remain central to union strategy for renewal in Australia and beyond.
Human Factors and Ergonomics Standards
Authors: Fox Robert , Sommerich Carolyn M. , Green Paul A. , Albin Thomas J. , Poston Alan M. , Gardner-Bonneau Daryle , Parsons Ken 
Published: October 2015

Have you ever wondered about HF/E standards – what they address, how to access them, how they are developed, and how they can help you in your job or research? Given the enhanced HFES focus on getting research into practice and how the desire for achieving that goal could affect the author instructions for HFES publications, this is a critical topic for both researchers and practitioners. Join us in this informative panel discussion to learn the answers to these and other questions about the world of HF/E standards activities. The panelists, representing the spectrum of HF/E standards involvement, will discuss the different standards development activities and the bodies that produce standards. Also discussed will be the unique challenges of standards work, including working with international colleagues, understanding and identifying stakeholders for standards works, and translating research and data into usable methods and information for practitioners. The discussion will conclude with information about how attendees can get involved in standards work.
Impact of Loading and Rest Intervals on Muscle Microtrauma
Authors: Smith Tianqi “Tenchi” Gao , Gallagher Sean 
Published: October 2015

The purpose of this study is to determine whether different rest intervals and load-repetition combinations with different frequencies and durations would have an impact on the microtrauma response of the muscle and the development of musculoskeletal disorders (MSDs). Serum Creatine Kinase (CK) level, the physical response measured in this study, is collected before exercise and at days 1, 2, 4, 8 post- eccentric exercise of the human elbow flexor muscles through phlebotomy and serum analysis. A two-factor (loading and rest interval) factorial regression model is established for muscle microtrauma response. The findings of the study would assist in understanding the effect of different rest intervals and load-repetition combinations on muscle microtrauma response and healing process to eccentric exercise, foster injury-prevention recommendations to manufacturing job design in terms of promoting rest intervals with suitable frequency, as well as force and repetition balance. The regression model could provide guidance to future ergonomic assessment tool design. The results of the study show that higher force with a low repetition frequency leads to greater response than lower force with high repetition frequency, when given a predetermined total work time, total rest time and total work volume. Though not greatly significant, experiment data show that longer rest intervals, although given less frequently, discourages the peak response of muscle microtrauma compared to shorter rest intervals given more frequently, when total work time, rest time and workload are predetermined.