bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emergence of sigh rhythmogenesis in the embryonic mouse
Authors: Chapuis Coralie , Autran Sandra , Fortin Gilles , Simmers John , Thoby‐Brisson Muriel 
Published: March 2014

Key points
The respiratory oscillator of the pre‐Bötzinger complex (preBötC) can generate distinct inspiratory motor patterns underlying eupnoeic and sigh‐related rhythmic activities.
The preBötC can generate ‘fictive’ eupnoea at embryonic stages, but its ability to also generate sigh‐like activity remains unexplored at prenatal stages.
Here, using mouse brainstem slice preparations, we show that sigh‐like activity emerges during embryonic development but later than eupnoeic rhythmogenesis. Inspiratory cells active during the latter are also active during fictive sighing, although a small subset of neurons was found to fire exclusively during sighs. Effective glycinergic inhibitory signalling is also required for sigh generation.
We conclude that the developmental emergence of a sigh‐generating capability occurs after the onset of eupnoeic rhythmogenesis and requires an appropriate maturational state of chloride‐mediated glycinergic synaptic transmission.
AbstractIn mammals, eupnoeic breathing is periodically interrupted by spontaneous augmented breaths (sighs) that include a larger‐amplitude inspiratory effort, typically followed by a post‐sigh apnoea. Previous in vitro studies in newborn rodents have demonstrated that the respiratory oscillator of the pre‐Bötzinger complex (preBötC) can generate the distinct inspiratory motor patterns for both eupnoea‐ and sigh‐related behaviour. During mouse embryonic development, the preBötC begins to generate eupnoeic rhythmicity at embryonic day (E) 15.5, but the network's ability to also generate sigh‐like activity remains unexplored at prenatal stages. Using transverse brainstem slice preparations we monitored the neuronal population activity of the preBötC at different embryonic ages. Spontaneous sigh‐like rhythmicity was found to emerge progressively, being expressed in 0/32 slices at E15.5, 7/30 at E16.5, 9/22 at E17.5 and 23/26 at E18.5. Calcium imaging showed that the preBötC cell population that participates in eupnoeic‐like discharge was also active during fictive sighs. However, patch‐clamp recordings revealed the existence of an additional small subset of neurons that fired exclusively during sigh activity. Changes in glycinergic inhibitory synaptic signalling, either by pharmacological blockade, functional perturbation or natural maturation of the chloride co‐transporters KCC2 or NKCC1 selectively, and in an age‐dependent manner, altered the bi‐phasic nature of sigh bursts and their coordination with eupnoeic bursting, leading to the generation of an atypical monophasic sigh‐related event. Together our results demonstrate that the developmental emergence of a sigh‐generating capability occurs after the onset of eupnoeic rhythmogenesis and requires the proper maturation of chloride‐mediated glycinergic synaptic transmission.
Computational analysis of Ca2+ dynamics in isolated cardiac mitochondria predicts two distinct modes of Ca2+ uptake
Authors: Tewari Shivendra G. , Camara Amadou K. S. , Stowe David F. , Dash Ranjan K. 
Published: March 2014

Key points
Cytosolic, but not matrix, Mg2+ inhibits mitochondrial Ca2+ uptake through the Ca2+ uniporter (CU).
The majority of mitochondrial Ca2+ uptake under physiological levels of cytosolic Ca2+ and Mg2+ is through a fast uptake pathway, namely the ryanodine receptor (RyR)‐type channel (RTC), that has characteristics similar to the ryanodine receptor.
Modulation of mitochondrial RTC adaptation and opening probability by cytosolic Mg2+ is not robust, in contrast to that of cardiac sarcoplasmic reticulum RyR.
Model analysis of the mitochondrial Ca2+ sequestration system further validates the existence of two different classes of Ca2+ buffering proteins, i.e. Class 1 and Class 2.
The Ca2+ buffering capacity of Class 1 protein is auto‐regulated by the rate at which Ca2+ is taken up by cardiac mitochondria.
The quantitative framework suggests differential roles for the two modes of Ca2+ uptake pathways: CU–Ca2+ buffering, and RTC–Ca2+ modulated bioenergetics.
AbstractCardiac mitochondria can act as a significant Ca2+ sink and shape cytosolic Ca2+ signals affecting various cellular processes, such as energy metabolism and excitation–contraction coupling. However, different mitochondrial Ca2+ uptake mechanisms are still not well understood. In this study, we analysed recently published Ca2+ uptake experiments performed on isolated guinea pig cardiac mitochondria using a computer model of mitochondrial bioenergetics and cation handling. The model analyses of the data suggest that the majority of mitochondrial Ca2+ uptake, at physiological levels of cytosolic Ca2+ and Mg2+, occurs through a fast Ca2+ uptake pathway, which is neither the Ca2+ uniporter nor the rapid mode of Ca2+ uptake. This fast Ca2+ uptake component was explained by including a biophysical model of the ryanodine receptor (RyR) in the computer model. However, the Mg2+‐dependent enhancement of the RyR adaptation was not evident in this RyR‐type channel, in contrast to that of cardiac sarcoplasmic reticulum RyR. The extended computer model is corroborated by simulating an independent experimental dataset, featuring mitochondrial Ca2+ uptake, egress and sequestration. The model analyses of the two datasets validate the existence of two classes of Ca2+ buffers that comprise the mitochondrial Ca2+ sequestration system. The modelling study further indicates that the Ca2+ buffers respond differentially depending on the source of Ca2+ uptake. In particular, it suggests that the Class 1 Ca2+ buffering capacity is auto‐regulated by the rate at which Ca2+ is taken up by mitochondria.
Novel approaches to determine contractile function of the isolated adult zebrafish ventricular cardiac myocyte
Authors: Dvornikov Alexey V. , Dewan Sukriti , Alekhina Olga V. , Pickett F. Bryan , de Tombe Pieter P. 
Published: March 2014

Key points
The zebrafish is emerging as an attractive cost‐effective model for the study of structure–function relationships. However, cardiac contractile function in the zebrafish remains to be investigated.
We applied novel approaches used to study contractile function at the cellular level in mammalian models to zebrafish. We found that contractile force regulation in the adult zebrafish shares many similarities with that in the mammalian myocardium as previously determined by others and ourselves, indicating that the zebrafish is an appropriate model system for the study of cardiac contractile biology.
AbstractThe zebrafish (Danio rerio) has been used extensively in cardiovascular biology, but mainly in the study of heart development. The relative ease of its genetic manipulation may indicate the suitability of this species as a cost‐effective model system for the study of cardiac contractile biology. However, whether the zebrafish heart is an appropriate model system for investigations pertaining to mammalian cardiac contractile structure–function relationships remains to be resolved. Myocytes were isolated from adult zebrafish hearts by enzymatic digestion, attached to carbon rods, and twitch force and intracellular Ca2+ were measured. We observed the modulation of twitch force, but not of intracellular Ca2+, by both extracellular [Ca2+] and sarcomere length. In permeabilized cells/myofibrils, we found robust myofilament length‐dependent activation. Moreover, modulation of myofilament activation–relaxation and force redevelopment kinetics by varied Ca2+ activation levels resembled that found previously in mammalian myofilaments. We conclude that the zebrafish is a valid model system for the study of cardiac contractile structure–function relationships.
Early prediction of tumor recurrence based on CT texture changes after stereotactic ablative radiotherapy (SABR) for lung cancer
Authors: Mattonen Sarah A. , Palma David A. , Haasbeek Cornelis J. A. , Senan Suresh , Ward Aaron D. 
Published: March 2014

Purpose:Benign computed tomography (CT) changes due to radiation induced lung injury (RILI) are common following stereotactic ablative radiotherapy (SABR) and can be difficult to differentiate from tumor recurrence. The authors measured the ability of CT image texture analysis, compared to more traditional measures of response, to predict eventual cancer recurrence based on CT images acquired within 5 months of treatment.Methods:A total of 24 lesions from 22 patients treated with SABR were selected for this study: 13 with moderate to severe benign RILI, and 11 with recurrence. Three‐dimensional (3D) consolidative and ground‐glass opacity (GGO) changes were manually delineated on all follow‐up CT scans. Two size measures of the consolidation regions (longest axial diameter and 3D volume) and nine appearance features of the GGO were calculated: 2 first‐order features [mean density and standard deviation of density (first‐order texture)], and 7 second‐order texture features [energy, entropy, correlation, inverse difference moment (IDM), inertia, cluster shade, and cluster prominence]. For comparison, the corresponding response evaluation criteria in solid tumors measures were also taken for the consolidation regions. Prediction accuracy was determined using the area under the receiver operating characteristic curve (AUC) and two‐fold cross validation (CV).Results:For this analysis, 46 diagnostic CT scans scheduled for approximately 3 and 6 months post‐treatment were binned based on their recorded scan dates into 2–5 month and 5–8 month follow‐up time ranges. At 2–5 months post‐treatment, first‐order texture, energy, and entropy provided AUCs of 0.79–0.81 using a linear classifier. On two‐fold CV, first‐order texture yielded 73% accuracy versus 76%–77% with the second‐order features. The size measures of the consolidative region, longest axial diameter and 3D volume, gave two‐fold CV accuracies of 60% and 57%, and AUCs of 0.72 and 0.65, respectively.Conclusions:Texture measures of the GGO appearance following SABR demonstrated the ability to predict recurrence in individual patients within 5 months of SABR treatment. Appearance changes were also shown to be more accurately predictive of recurrence, as compared to size measures within the same time period. With further validation, these results could form the substrate for a clinically useful computer‐aided diagnosis tool which could provide earlier salvage of patients with recurrence.
Alteration of the Murine Gastrointestinal Microbiota by Tigecycline Leads to Increased Susceptibility to Clostridium difficile Infection
Authors: Bassis Christine M. , Theriot Casey M. , Young Vincent B. 
Published: March 2014

ABSTRACT

Antibiotics can play dual roles in
Clostridium difficile
infection (CDI); antibiotic treatment increases the risk of CDI, and antibiotics are used to treat CDI. The glycylcycline antibiotic tigecycline has broad antimicrobial activity, yet it is rarely associated with the development of CDI, presumably due to its activity against
C. difficile
. In this study, we investigated how tigecycline treatment affects the structure of the gut microbiota and susceptibility to CDI by treating mice with tigecycline (
n
= 20) or saline (
n
= 8) for 10 days. A sequence analysis of the bacterial 16S rRNA gene amplicons was used to monitor changes in the fecal microbiota. A subset of the mice was followed for 5 weeks after the end of treatment. The remaining mice were challenged with
C. difficile
strain VPI 10463 spores 2 days after the tigecycline treatment ended. Tigecycline treatment resulted in major shifts in the gut microbiota, including large decreases in
Bacteroidetes
levels and large increases in
Proteobacteria
levels. Mice with tigecycline-altered microbial communities were susceptible to challenge with
C. difficile
spores and developed clinical signs of severe CDI. Five weeks after the cessation of tigecycline treatment, the recovery of the bacterial community was incomplete and diversity was lower than in the untreated controls. Antibiotics with intrinsic activity against
C. difficile
can still alter the microbiota in a way that leads to susceptibility to CDI after discontinuation of the drug. These results indicate that microbiotic dynamics are key in the development of CDI, and a better understanding of these dynamics may lead to better strategies to prevent and treat this disease.
Antimicrobial Treatment Improves Mycobacterial Survival in Nonpermissive Growth Conditions
Authors: Turapov Obolbek , Waddell Simon J. , Burke Bernard , Glenn Sarah , Sarybaeva Asel A. , Tudo Griselda , Labesse Gilles , Young Danielle I. , Young Michael , Andrew Peter W. , Butcher Philip D. , Cohen-Gonsaud Martin , Mukamolova Galina V. 
Published: March 2014

ABSTRACT

Antimicrobials targeting cell wall biosynthesis are generally considered inactive against nonreplicating bacteria. Paradoxically, we found that under nonpermissive growth conditions, exposure of
Mycobacterium bovis
BCG bacilli to such antimicrobials enhanced their survival. We identified a transcriptional regulator, RaaS (for regulator of antimicrobial-assisted survival), encoded by
bcg1279
(
rv1219c
) as being responsible for the observed phenomenon. Induction of this transcriptional regulator resulted in reduced expression of specific ATP-dependent efflux pumps and promoted long-term survival of mycobacteria, while its deletion accelerated bacterial death under nonpermissive growth conditions
in vitro
and during macrophage or mouse infection. These findings have implications for the design of antimicrobial drug combination therapies for persistent infectious diseases, such as tuberculosis.
Setting the stage for the genesis of the giant Bendigo ore system
Authors: Bull Stuart W. , Large Ross R. 
Published: March 2014

Abstract
The Ordovician sediments that host the giant Bendigo saddle reef gold deposits consist of a 3 km-thick sequence of turbiditic sandstones and interbedded siltstones and mudstones. Sedimentological studies suggest the succession formed within a major deep marine channel–levee complex similar to those described from contemporary continental margin to basin plain settings outboard of major river systems (e.g. the Amazon, Mississippi and Congo). Black shales, which are commonly the immediate host rocks to the epigenetic gold reefs, are interpreted to be over-bank deposits or abandoned channel fills, developed adjacent to active channels which were sandstone-dominated and had an incised axial thalweg marked by the coarsest-grained sediments present.
Organic carbon content of the black shales at Bendigo varies from 0.2 to 2 wt%, compared with the grey shales, siltstones and sandstones, which vary from 0.05 to 0.2 wt%. Trace elements fall into two main groups: (a) elements that have a linear relationship with aluminium, and are controlled by the detrital clay content (Sn, Ba, Rb, Li, Cs, Mn, Cr and Tl); and (b) elements that show relationships with both aluminium and organic carbon (V, U, Ni, Zn, Cu, Bi, Pb, Se, Ag and Au) and are controlled by both the clay and organic matter content in the carbonaceous shales. The elements in the second group are enriched in the black shale facies.
The background gold content of the black shales in the drill holes distal from mineralization averages 8.9 ppb, compared with the sandstones with 1.5 ppb. Most of the gold in the shales is present in diagenetic pyrite and marcasite, which laser ablation inductively coupled mass spectrometer (LA-ICPMS) analyses indicate varies from 5 to 3850 ppb and averages 370 ppb Au. The geochemical data suggest that this syngenetic gold was most likely sourced by erosion of the hinterland, and transported attached to detrital clay particles or as colloidal gold, by a high-volume feeder river system. High Rb/K ratios in the shales support a highly weathered source typical of a giant river system. By analogy with modern systems, following transport into deep marine channel–levee complexes via continental margin canyons, gold and other redox sensitive trace elements were ultimately trapped by reduction, adsorption and complexation with organic matter in the sub-oxic to anoxic over-bank deposits. Oxidation of much of the organic matter during diagenesis released the gold and certain trace elements (Ni, Co, Se, Ag, Cu, Bi, Pb), which became incorporated into diagenetic pyrite. Enrichment of gold in diagenetic pyrite of the black shale facies of the Ordovician turbidites at Bendigo was the first stage in a two-stage process that produced the world-class quartz–gold saddle reef deposits.

Supplementary material:

Whole rock analyses for sedimentary rocks in drill holes NBD005 and NBD186, Kangaroo Flat Mine, Bendigo, are available at
http://www.geolsoc.org.uk/SUP18732
Development and Implementation of Wireless Multigas Concentration Cloud System
Authors: Tien Sheng-Chung , Lin Robert , Lee Tsung-Yu , Lee Ren-Guey , Huang Shu-Ying 
Published: March 2014

According to the report “Global Health Risks of 2004” issued by WHO (World Health Organization) in Geneva 2009 (WHO, 2012),	the mortality rate of the diseases and cause of death which results from the smoke produced by burning solid fuel is ranked tenth, occupying 3.3% of the global amounts, and the DALYs (Disability Adjusted Life Years) is ranked the ninth, occupying 2.7% of the world. Once the pollution occurred in an insufficient ventilation location, the womankind and children will be the most directly affected; therefore, we hoped to focus the measurement environment on indoor surroundings in this paper. This paper proposes a pointing at several kinds of indoor pollutants and integrating multigas sensors, which includes carbon monoxide, carbon dioxide total volatile organic compounds, and so forth. Our paper combines gas sensors with WSN (Wireless Sensor Networks) nodes; we provide users with optional monitoring subjects for constructing and also adapt ZigBee and Wi-Fi modules to get united with uploading real-time sensor messages. Moreover, for the reason of decreasing installation cost of sensors and setting up easily, this paper builds a cloud data-viewing platform additionally, enabling users to observe air quality through the cloud server everywhere.
Undiagnosed Diabetes in Breast, Colorectal, Lung, and Prostate Cancer: Incidence and Risk Factors
Authors: Griffiths Robert I. , Lindquist Karla J. , O’Malley Cynthia D. , Gleeson Michelle L. , Duryea Jennifer L. , Valderas José M. , Danese Mark D. 
Published: March 2014

Our study describes the incidence and risk factors for undiagnosed diabetes in elderly cancer patients. Using Surveillance, Epidemiology, and End Results-Medicare data, we followed patients with breast, colorectal, lung, or prostate cancer from 24 months before to 3 months after cancer diagnosis. Medicare claims were used to exclude patients with diabetes 24 to 4 months before cancer (look-back period), identify those with diabetes undiagnosed until cancer, and construct indicators of preventive services, physician contact, and comorbidity during the look-back period. Logistic regression analyses were performed to identify factors associated with undiagnosed diabetes. Overall, 2,678 patients had diabetes undiagnosed until cancer. Rates were the highest in patients with both advanced-stage cancer and low prior primary care/medical specialist contact (breast 8.2%, colorectal 5.9%, lung 4.4%). Nonwhite race/ethnicity, living in a census tract with a higher percent of the population in poverty and a lower percent college educated, lower prior preventive services use, and lack of primary care and/or medical specialist care prior to cancer all were associated with higher (P≤0.05) adjusted odds of undiagnosed diabetes. Undiagnosed diabetes is relatively common in selected subgroups of cancer patients, including those already at high risk of poor outcomes due to advanced cancer stage.
The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential
Authors: Beltran Himisha 
Published: March 2014

Abstract
N-myc (MYCN), a member of the Myc family of basic-helix–loop–helix–zipper (bHLHZ) transcription factors, is a central regulator of many vital cellular processes. As such, N-myc is well recognized for its classic oncogenic activity and association with human neuroblastoma. Amplification and overexpression of N-myc has been described in other tumor types, particularly those of neural origin and neuroendocrine tumors. This review outlines N-myc's contribution to normal development and oncogenic progression. In addition, it highlights relevant transcriptional targets and mechanisms of regulation. Finally, the clinical implications of N-Myc as a biomarker and potential as a target using novel therapeutic approaches are discussed. Mol Cancer Res; 12(6); 815–22. ©2014 AACR.
MYC, MAX, and Small Cell Lung Cancer
Authors: Rudin Charles M. , Poirier J.T. 
Published: March 2014

Abstract
Summary: In this issue of Cancer Discovery, Romero and colleagues identify somatic mutations and deletions of MAX, and also define what seem to be mutually exclusive alterations in MYC family members and other MYC-associated factors in small cell lung cancer. Taken together, these data highlight the importance of MYC signaling in small cell lung cancer and suggest possible avenues for therapeutic intervention. Cancer Discov; 4(3); 273–4. ©2014 AACR.
See related article by Romero et al., p. 292
Forecast: Rough Seas for Leukemia
Authors: Hockenbery David M. 
Published: March 2014

Abstract
Summary: Expression of BCL-2, BCL-XL, and MCL-1 in acute myelogenous leukemia is highly variable. Cellular BH3 profiling can help decide which are likely to respond to BCL-2–targeted BH3 mimetics. Cancer Discov; 4(3); 278–9. ©2014 AACR.
See related article by Pan et al., p. 362
Cancer–Testis Antigen 7 Expression and Immune Responses Following Allogeneic Stem Cell Transplantation for Multiple Myeloma
Authors: Tyler Eleanor M. , Jungbluth Achim A. , Gnjatic Sacha , O'Reilly Richard J. , Koehne Guenther 
Published: March 2014

Abstract
Cancer–testis antigen 7 (CT7) is the most frequently and consistently expressed MAGE antigen in multiple myeloma, exhibits tissue-restricted expression, and is an independent negative prognostic factor for multiple myeloma. We sought to characterize CT7 protein expression in the bone marrow of patients with multiple myeloma undergoing allogeneic T cell–depleted hematopoietic stem cell transplantation (alloTCD-HSCT), and to examine the significance of CT7-specific cellular immune responses. We further aimed to determine CT7-derived immunogenic epitopes and their associated allelic restrictions. CT7 protein expression in neoplastic CD138+ plasma cells was evaluated by immunohistochemistry in bone marrow biopsies from 10 patients. CT7 was present in 8 of 10 patients. Longitudinal analyses of the 10 patients revealed an association between CT7 expression and prognosis. Longitudinal monitoring of CT7-specific T cells revealed an association between increased frequencies of CT7-specific T cells and reductions in specific myeloma markers. Epitope-specific reactivity to the nonamer FLAMLKNTV was detected by intracellular IFNγ assay in peripheral blood (PB) and bone marrow–derived T cells from HLA-A*0201+ patients. Serial monitoring of PB CT7-specific T-cell frequencies in 4 HLA-A*0201+ patients by HLA-A*0201-CT7(1087–1095) tetramer staining revealed an association with disease course. Phenotypic analyses revealed bone marrow enrichment for central memory CT7-specific T cells, while effector memory cells dominated the PB. Together, these findings support the development of immunotherapeutic strategies that aim to enhance CT7-directed immune responses for the treatment of multiple myeloma. Cancer Immunol Res; 2(6); 547–58. ©2014 AACR.