bluuebunny/crossref_metadata_2025 huggingface dataset:
The Australian Palliative Care Outcomes Collaboration (PCOC) - measuring the quality and outcomes of palliative care on a routine basis
Authors: Eagar Kathy , Watters Prue , Currow David C. , Aoun Samar M. , Yates Patsy
Published: May 2010

Australia is leading the way in establishing a national system (the Palliative Care Outcomes Collaboration – PCOC) to measure the outcomes and quality of specialist palliative care services and to benchmark services across the country. This article reports on analysis of data collected routinely at point-of-care on 5939 patients treated by the first fifty one services that voluntarily joined PCOC. By March 2009, 111 services have agreed to join PCOC, representing more than 70% of services and more than 80% of specialist palliative care patients nationally. All states and territories are involved in this unique process that has involved extensive consultation and infrastructure and close collaboration between health services and researchers.
The challenges of dealing with wide variation in outcomes and practice and the progress achieved to date are described. PCOC is aiming to improve understanding of the reasons for variations in clinical outcomes between specialist palliative care patients and differences in service outcomes as a critical step in an ongoing process to improve both service quality and patient outcomes.
What is known about the topic?Governments internationally are grappling with how best to provide care for people with life limiting illnesses and how best to measure the outcomes and quality of that care. There is little international evidence on how to measure the quality and outcomes of palliative care on a routine basis.
What does this paper add?The Palliative Care Outcomes Collaboration (PCOC) is the first effort internationally to measure the outcomes and quality of specialist palliative care services and to benchmark services on a national basis through an independent third party.
What are the implications for practitioners?If outcomes and quality are to be measured on a consistent national basis, standard clinical assessment tools that are used as part of everyday clinical practice are necessary.
An integrative review of the role of registered nurses in remote and isolated practice
Authors: Coyle Meaghan , Al-Motlaq Mohammad A. , Mills Jane , Francis Karen , Birks Melanie
Published: May 2010

Objective.To examine the role of the registered nurse in remote and isolated areas of Queensland, the Northern Territory, South Australia and Western Australia; and to illustrate the impact of the burden of disease on nursing practice. Data sources.A literature search was undertaken using electronic databases and the grey literature (including policy documents, project reports and position descriptions). Data synthesis.The role of the nurse in remote areas is diverse, and varies according to the context of practice. Although some states and territories offer formal programs to prepare nurses for the role, it is unclear whether this is routinely provided. The burden of disease is higher in remote Australia, and although nurses work to reduce the burden, the need to provide primary care can be at the expense of primary health care. Conclusions.Whilst the nature of nursing practice is influenced by many factors, considerable agreement exists between states and territories around the role of the registered nurses in remote and isolated communities. The higher burden of disease in remote and isolated areas of Australia impacts on nursing practice, and nurses are uniquely placed to assist in reducing the burden of disease. Greater agreement around what constitutes ‘remote’ is needed. What is known about the topic?Many papers have reported on the difficulties encountered by registered nurses in remote and isolated practice; however, there is a dearth of information describing the role of registered nurses in remote or isolated Australian communities. What does this paper add?This review describes the diverse role of nurses and their role in addressing the burden of disease in remote and isolated Australia. Comparison between states and territories highlights differences in preparation for the role. What are the implications for practitioners?National agreement is needed around preparation for practice, conditions of work, and what constitutes ‘remote’. Greater utilisation of the nursing workforce in remote and isolated areas would assist in addressing the burden of disease.
Maximising the value of hospital administrative datasets
Authors: Nadathur Shyamala G.
Published: May 2010

Mandatory and standardised administrative data collections are prevalent in the largely public-funded acute sector. In these systems the data collections are used for financial, performance monitoring and reporting purposes. This paper comments on the infrastructure and standards that have been established to support data collection activities, audit and feedback. The routine, local and research uses of these datasets are described using examples from Australian and international literature. The advantages of hospital administrative datasets and opportunities for improvement are discussed under the following headings: accessibility, standardisation, coverage, completeness, cost of obtaining clinical data, recorded Diagnostic Related Groups and International Classification of Diseases codes, linkage and connectivity. In an era of diminishing resources better utilisation of these datasets should be encouraged. Increased study and scrutiny will enhance transparency and help identify issues in the collections. As electronic information systems are increasingly embraced, administrative data collections need to be managed as valuable assets and powerful operational and patient management tools.
Is Western Australia representative of other Australian States and Territories in terms of key socio-demographic and health economic indicators?
Authors: Clark Antony , Preen David B. , Ng Jonathon Q. , Semmens James B. , Holman C. D'Arcy J.
Published: May 2010

Objective.To evaluate the extent to which Western Australian (WA) represents the broader Australian population in terms of key socio-demographic and health economic indicators. Methods.We compared key demographic, social and health economic indicators across all Australian States and Territories from Australian government publications in the census years 1991–2006. Jurisdictional averages (JAs) were calculated as the mean (±s.d.) or median (±range). Observed jurisdiction indicators were compared with the JA and ranked according its representativeness of the JA. Results.WA was among the three closest jurisdictions to the national JA for all socio-demographic and health economic indicators examined, with the exception of uptake of private health insurance (ranked 6th) and per-capita health expenditure (ranked 5th). The Northern Territory and Australian Capital Territory were least representative for the majority of indicators. Excluding the proportions of people living in rural or remote areas (0–100%) and of indigenous origin (0.4–28.8%), variations in the indicators across the jurisdictions were relatively small. Conclusions.Population differences between Australia’s States were small, whereas Australia’s Territories were least representative of the JA. WA was the most representative population of Australia’s eight jurisdictions and continues to be in a strong position to contribute to knowledge of the Australian health system that is applicable Australia-wide. What is known about the topic?The Western Australian Data Linkage system (WADLS) is a highly successful and productive research tool that facilitates population-based health research. A potential criticism and concern of this research surrounds the representativeness of the WA population to other Australian States and Territories. Anecdotally, there is a perception that WA’s isolation from other Australian populations may lead to systematic socio-demographic and socioeconomic differences; thus limiting the generalisability of research findings. What does this paper add?This paper compares Australia’s State and Territory population profiles and allows researchers to determine the extent to which contextual issues concerning key socio-demographic and health economic indicators may affect the external validity of population-based research arising from any one jurisdiction. What are the implications to practitioners?In the absence of previous evaluations in this area and with the continued emergence of new data linkage systems around the country, this information is important for health researchers and policy makers who may wish to draw conclusions and make policy decisions that rely upon extrapolating findings from population-based studies.
Grb2 functions at the top of the T-cell antigen receptor–induced tyrosine kinase cascade to control thymic selection
Authors: Jang Ihn Kyung , Zhang Jinping , Chiang Yungping J. , Kole Hemanta K. , Cronshaw Darran G. , Zou Yongrui , Gu Hua
Published: May 2010

Grb2 is an adaptor molecule that mediates Ras-MAPK activation induced by various receptors. Here we show that conditional ablation of Grb2 in thymocytes severely impairs both thymic positive and negative selections. Strikingly, the mutation attenuates T-cell antigen receptor (TCR) proximal signaling, including tyrosine phosphorylation of multiple signaling proteins and Ca
2+
influx. The defective TCR signaling can be attributed to a marked impairment in Lck activation. Ectopic expression of a mutant Grb2 composed of the central SH2 and the C-terminal SH3 domains in Grb2
−/−
thymocytes fully restores thymocyte development. Thus, Grb2 plays a pivotal role in both thymic positive and negative selection. It amplifies TCR signaling at the top end of the tyrosine phosphorylation cascade via a scaffolding function.
Testosterone decreases trust in socially naïve humans
Authors: Bos Peter A. , Terburg David , van Honk Jack
Published: May 2010

Trust plays an important role in the formation and maintenance of human social relationships. But trusting others is associated with a cost, given the prevalence of cheaters and deceivers in human society. Recent research has shown that the peptide hormone oxytocin increases trust in humans. However, oxytocin also makes individuals susceptible to betrayal, because under influence of oxytocin, subjects perseverate in giving trust to others they know are untrustworthy. Testosterone, a steroid hormone associated with competition and dominance, is often viewed as an inhibitor of sociality, and may have antagonistic properties with oxytocin. The following experiment tests this possibility in a placebo-controlled, within-subjects design involving the administration of testosterone to 24 female subjects. We show that compared with the placebo, testosterone significantly decreases interpersonal trust, and, as further analyses established, this effect is determined by those who give trust easily. We suggest that testosterone adaptively increases social vigilance in these trusting individuals to better prepare them for competition over status and valued resources. In conclusion, our data provide unique insights into the hormonal regulation of human sociality by showing that testosterone downregulates interpersonal trust in an adaptive manner.
History of biological metal utilization inferred through phylogenomic analysis of protein structures
Authors: Dupont Christopher L. , Butcher Andrew , Valas Ruben E. , Bourne Philip E. , Caetano-Anollés Gustavo
Published: May 2010

The fundamental chemistry of trace elements dictates the molecular speciation and reactivity both within cells and the environment at large. Using protein structure and comparative genomics, we elucidate several major influences this chemistry has had upon biology. All of life exhibits the same proteome size-dependent scaling for the number of metal-binding proteins within a proteome. This fundamental evolutionary constant shows that the selection of one element occurs at the exclusion of another, with the eschewal of Fe for Zn and Ca being a defining feature of eukaryotic proteomes. Early life lacked both the structures required to control intracellular metal concentrations and the metal-binding proteins that catalyze electron transport and redox transformations. The development of protein structures for metal homeostasis coincided with the emergence of metal-specific structures, which predominantly bound metals abundant in the Archean ocean. Potentially, this promoted the diversification of emerging lineages of Archaea and Bacteria through the establishment of biogeochemical cycles. In contrast, structures binding Cu and Zn evolved much later, providing further evidence that environmental availability influenced the selection of the elements. The late evolving Zn-binding proteins are fundamental to eukaryotic cellular biology, and Zn bioavailability may have been a limiting factor in eukaryotic evolution. The results presented here provide an evolutionary timeline based on genomic characteristics, and key hypotheses can be tested by alternative geochemical methods.
WASH and WAVE actin regulators of the Wiskott–Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes
Authors: Jia Da , Gomez Timothy S. , Metlagel Zoltan , Umetani Junko , Otwinowski Zbyszek , Rosen Michael K. , Billadeau Daniel D.
Published: May 2010

We recently showed that the Wiskott–Aldrich syndrome protein (WASP) family member, WASH, localizes to endosomal subdomains and regulates endocytic vesicle scission in an Arp2/3-dependent manner. Mechanisms regulating WASH activity are unknown. Here we show that WASH functions in cells within a 500 kDa core complex containing Strumpellin, FAM21, KIAA1033 (SWIP), and CCDC53. Although recombinant WASH is constitutively active toward the Arp2/3 complex, the reconstituted core assembly is inhibited, suggesting that it functions in cells to regulate actin dynamics through WASH. FAM21 interacts directly with CAPZ and inhibits its actin-capping activity. Four of the five core components show distant (approximately 15% amino acid sequence identify) but significant structural homology to components of a complex that negatively regulates the WASP family member, WAVE. Moreover, biochemical and electron microscopic analyses show that the WASH and WAVE complexes are structurally similar. Thus, these two distantly related WASP family members are controlled by analogous structurally related mechanisms. Strumpellin is mutated in the human disease hereditary spastic paraplegia, and its link to WASH suggests that misregulation of actin dynamics on endosomes may play a role in this disorder.
Process-based network decomposition reveals backbone motif structure
Authors: Wang Guanyu , Du Chenghang , Chen Hao , Simha Rahul , Rong Yongwu , Xiao Yi , Zeng Chen
Published: May 2010

A central challenge in systems biology today is to understand the network of interactions among biomolecules and, especially, the organizing principles underlying such networks. Recent analysis of known networks has identified small motifs that occur ubiquitously, suggesting that larger networks might be constructed in the manner of electronic circuits by assembling groups of these smaller modules. Using a unique process-based approach to analyzing such networks, we show for two cell-cycle networks that each of these networks contains a giant backbone motif spanning all the network nodes that provides the main functional response. The backbone is in fact the smallest network capable of providing the desired functionality. Furthermore, the remaining edges in the network form smaller motifs whose role is to confer stability properties rather than provide function. The process-based approach used in the above analysis has additional benefits: It is scalable, analytic (resulting in a single analyzable expression that describes the behavior), and computationally efficient (all possible minimal networks for a biological process can be identified and enumerated).
NADPH oxidase activity controls phagosomal proteolysis in macrophages through modulation of the lumenal redox environment of phagosomes
Authors: Rybicka Joanna M. , Balce Dale R. , Khan Morgan F. , Krohn Regina M. , Yates Robin M.
Published: May 2010

The phagosomal lumen in macrophages is the site of numerous interacting chemistries that mediate microbial killing, macromolecular degradation, and antigen processing. Using a non-hypothesis-based screen to explore the interconnectivity of phagosomal functions, we found that NADPH oxidase (NOX2) negatively regulates levels of proteolysis within the maturing phagosome of macrophages. Unlike the NOX2 mechanism of proteolytic control reported in dendritic cells, this phenomenon in macrophages is independent of changes to lumenal pH and is also independent of hydrolase delivery to the phagosome. We found that NOX2 mediates the inhibition of phagosomal proteolysis in macrophages through reversible oxidative inactivation of local cysteine cathepsins. We also show that NOX2 activity significantly compromises the phagosome's ability to reduce disulfides. These findings indicate that NOX2 oxidatively inactivates cysteine cathepsins through sustained ablation of the reductive capacity of the phagosomal lumen. This constitutes a unique mechanism of spatiotemporal control of phagosomal chemistries through the modulation of the local redox environment. In addition, this work further implicates the microbicidal effector NOX2 as a global modulator of phagosomal physiologies, particularly of those pertinent to antigen processing.
Signal-dependent turnover of the bacterial flagellar switch protein FliM
Authors: Delalez Nicolas J. , Wadhams George H. , Rosser Gabriel , Xue Quan , Brown Mostyn T. , Dobbie Ian M. , Berry Richard M. , Leake Mark C. , Armitage Judith P.
Published: May 2010

Most biological processes are performed by multiprotein complexes. Traditionally described as static entities, evidence is now emerging that their components can be highly dynamic, exchanging constantly with cellular pools. The bacterial flagellar motor contains ∼13 different proteins and provides an ideal system to study functional molecular complexes. It is powered by transmembrane ion flux through a ring of stator complexes that push on a central rotor. The
Escherichia coli
motor switches direction stochastically in response to binding of the response regulator CheY to the rotor switch component FliM. Much is known of the static motor structure, but we are just beginning to understand the dynamics of its individual components. Here we measure the stoichiometry and turnover of FliM in functioning flagellar motors, by using high-resolution fluorescence microscopy of
E. coli
expressing genomically encoded YPet derivatives of FliM at physiological levels. We show that the ∼30 FliM molecules per motor exist in two discrete populations, one tightly associated with the motor and the other undergoing stochastic turnover. This turnover of FliM molecules depends on the presence of active CheY, suggesting a potential role in the process of motor switching. In many ways the bacterial flagellar motor is as an archetype macromolecular assembly, and our results may have further implications for the functional relevance of protein turnover in other large molecular complexes.
Trophic position influences the efficacy of seabirds as metal biovectors
Authors: Michelutti Neal , Blais Jules M. , Mallory Mark L. , Brash Jaclyn , Thienpont Joshua , Kimpe Lynda E. , Douglas Marianne S. V. , Smol John P.
Published: May 2010

Seabirds represent a well documented biological transport pathway of nutrients from the ocean to the land by nesting in colonies and providing organic subsidies (feces, carcasses, dropped food) to these sites. We investigated whether seabirds that feed at different trophic levels vary in their potency as biovectors of metals, which can bioaccumulate through the marine foodweb. Our study site, located on a small island in Arctic Canada, contains the unique scenario of two nearby ponds, one of which receives inputs almost exclusively from upper trophic level piscivores (Arctic terns,
Sterna paradisaea
) and the other mainly from lower trophic level molluscivores (common eiders,
Somateria mollissima
). We used dated sediment cores to compare differences in diatoms, metal concentrations and also stable isotopes of nitrogen (δ
15
N), which reflect trophic position. We show that the seabirds carry species-specific mixtures of metals that are ultimately shunted to their nesting sites. For example, sediments from the tern-affected pond recorded the highest levels of δ
15
N and the greatest concentrations of metals that are known to bioaccumulate, including Hg and Cd. In contrast, the core from the eider-affected site registered lower δ
15
N values, but higher concentrations of Pb, Al, and Mn. These metals have been recorded at their greatest concentrations in eiders relative to other seabirds, including Arctic terns. These data indicate that metals may be used to track seabird population dynamics, and that some metal tracers may even be species-specific. The predominance of large seabird colonies on every continent suggests that similar processes are operating along coastlines worldwide.
Membrane domain structures of three classes of histidine kinase receptors by cell-free expression and rapid NMR analysis
Authors: Maslennikov Innokentiy , Klammt Christian , Hwang Eunha , Kefala Georgia , Okamura Mizuki , Esquivies Luis , Mörs Karsten , Glaubitz Clemens , Kwiatkowski Witek , Jeon Young Ho , Choe Senyon
Published: May 2010

NMR structural studies of membrane proteins (MP) are hampered by complications in MP expression, technical difficulties associated with the slow process of NMR spectral peak assignment, and limited distance information obtainable for transmembrane (TM) helices. To overcome the inherent challenges in the determination of MP structures, we have developed a rapid and cost-efficient strategy that combines cell-free (CF) protein synthesis, optimized combinatorial dual-isotope labeling for nearly instant resonance assignment, and fast acquisition of long-distance information using paramagnetic probes. Here we report three backbone structures for the TM domains of the three classes of
Escherichia coli
histidine kinase receptors (HKRs). The ArcB and QseC TM domains are both two-helical motifs, whereas the KdpD TM domain comprises a four-helical bundle with shorter second and third helices. The interhelical distances (up to 12 Å) reveal weak interactions within the TM domains of all three receptors. Determined consecutively within 8 months, these structures offer insight into the abundant and underrepresented in the Protein Data Bank class of 2–4 TM crossers and demonstrate the efficiency of our CF combinatorial dual-labeling strategy, which can be applied to solve MP structures in high numbers and at a high speed. Our results greatly expand the current knowledge of HKR structure, opening the doors to studies on their widespread and pharmaceutically important bacterial signaling mechanism.
Vascular Robo4 restricts proangiogenic VEGF signaling in breast
Authors: Marlow Rebecca , Binnewies Mikhail , Sorensen Lise K. , Monica Stefanie D. , Strickland Phyllis , Forsberg E. Camilla , Li Dean Y. , Hinck Lindsay
Published: May 2010

Formation of the vascular system within organs requires the balanced action of numerous positive and negative factors secreted by stromal and epithelial cells. Here, we used a genetic approach to determine the role of SLITs in regulating the growth and organization of blood vessels in the mammary gland. We demonstrate that vascularization of the gland is not affected by loss of
Slit
expression in the epithelial compartment. Instead, we identify a stromal source of SLIT, mural cells encircling blood vessels, and show that loss of
Slit
in the stroma leads to elevated blood vessel density and complexity. We examine candidate SLIT receptors,
Robo1
and
Robo4
, and find that increased vessel angiogenesis is phenocopied by loss of endothelial-specific
Robo4
, as long as it is combined with the presence of an angiogenic stimulus such as preneoplasia or pregnancy. In contrast, loss of
Robo1
does not affect blood vessel growth. The enhanced growth of blood vessels in
Robo4
−/−
endothelium is due to activation of vascular endothelial growth factor (VEGF)-R2 signaling through the Src and FAK kinases. Thus, our studies present a genetic dissection of SLIT/ROBO signaling during organ development. We identify a stromal, rather than epithelial, source of SLITs that inhibits blood vessel growth by signaling through endothelial ROBO4 to down-regulate VEGF/VEGFR2 signaling.
Synthesis of the 2Fe subcluster of the [FeFe]-hydrogenase H cluster on the HydF scaffold
Authors: Shepard Eric M. , McGlynn Shawn E. , Bueling Alexandra L. , Grady-Smith Celestine S. , George Simon J. , Winslow Mark A. , Cramer Stephen P. , Peters John W. , Broderick Joan B.
Published: May 2010

The organometallic H cluster at the active site of [FeFe]-hydrogenase consists of a 2Fe subcluster coordinated by cyanide, carbon monoxide, and a nonprotein dithiolate bridged to a [4Fe-4S] cluster via a cysteinate ligand. Biosynthesis of this cluster requires three accessory proteins, two of which (HydE and HydG) are radical
S
-adenosylmethionine enzymes. The third, HydF, is a GTPase. We present here spectroscopic and kinetic studies of HydF that afford fundamental new insights into the mechanism of H-cluster assembly. Electron paramagnetic spectroscopy reveals that HydF binds both [4Fe-4S] and [2Fe-2S] clusters; however, when HydF is expressed in the presence of HydE and HydG (HydF
EG
), only the [4Fe-4S] cluster is observed by EPR. Insight into the fate of the [2Fe-2S] cluster harbored by HydF is provided by FTIR, which shows the presence of carbon monoxide and cyanide ligands in HydF
EG
. The thorough kinetic characterization of the GTPase activity of HydF shows that activity can be gated by monovalent cations and further suggests that GTPase activity is associated with synthesis of the 2Fe subcluster precursor on HydF, rather than with transfer of the assembled precursor to hydrogenase. Interestingly, we show that whereas the GTPase activity is independent of the presence of the FeS clusters on HydF, GTP perturbs the EPR spectra of the clusters, suggesting communication between the GTP- and cluster-binding sites. Together, the results indicate that the 2Fe subcluster of the H cluster is synthesized on HydF from a [2Fe-2S] cluster framework in a process requiring HydE, HydG, and GTP.
Arrested phase separation in reproducing bacteria creates a generic route to pattern formation
Authors: Cates M. E. , Marenduzzo D. , Pagonabarraga I. , Tailleur J.
Published: May 2010

We present a generic mechanism by which reproducing microorganisms, with a diffusivity that depends on the local population density, can form stable patterns. For instance, it is known that a decrease of bacterial motility with density can promote separation into bulk phases of two coexisting densities; this is opposed by the logistic law for birth and death that allows only a single uniform density to be stable. The result of this contest is an arrested nonequilibrium phase separation in which dense droplets or rings become separated by less dense regions, with a characteristic steady-state length scale. Cell division predominates in the dilute regions and cell death in the dense ones, with a continuous flux between these sustained by the diffusivity gradient. We formulate a mathematical model of this in a case involving run-and-tumble bacteria and make connections with a wider class of mechanisms for density-dependent motility. No chemotaxis is assumed in the model, yet it predicts the formation of patterns strikingly similar to some of those believed to result from chemotactic behavior.
Tubulin polyglutamylation is essential for airway ciliary function through the regulation of beating asymmetry
Authors: Ikegami Koji , Sato Showbu , Nakamura Kenji , Ostrowski Lawrence E. , Setou Mitsutoshi
Published: May 2010

Airway epithelial cilia protect the mammalian respiratory system from harmful inhaled materials by providing the force necessary for effective mucociliary clearance. Ciliary beating is asymmetric, composed of clearly distinguished effective and recovery strokes. Neither the importance of nor the essential components responsible for the beating asymmetry has been directly elucidated. We report here that the beating asymmetry is crucial for ciliary function and requires tubulin glutamylation, a unique posttranslational modification that is highly abundant in cilia. WT murine tracheal cilia have an axoneme-intrinsic structural curvature that points in the direction of effective strokes. The axonemal curvature was lost in tracheal cilia from mice with knockout of a tubulin glutamylation-performing enzyme, tubulin tyrosine ligase-like protein 1. Along with the loss of axonemal curvature, the axonemes and tracheal epithelial cilia from these knockout (KO) mice lost beating asymmetry. The loss of beating asymmetry resulted in a reduction of cilia-generated fluid flow in trachea from the KO mice. The KO mice displayed a significant accumulation of mucus in the nasal cavity, and also emitted frequent coughing- or sneezing-like noises. Thus, the beating asymmetry is important for airway ciliary function. Our find-ings provide evidence that tubulin glutamylation is essential for ciliary function through the regulation of beating asymmetry, and provides insight into the molecular basis underlying the beating asymmetry.
Ca
V
3.1 is a tremor rhythm pacemaker in the inferior olive
Authors: Park Young-Gyun , Park Hye-Yeon , Lee C. Justin , Choi Soonwook , Jo Seonmi , Choi Hansol , Kim Yang-Hann , Shin Hee-Sup , Llinas Rodolfo R. , Kim Daesoo
Published: May 2010

The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of Ca
V
3.1 T-type Ca
2+
channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking Ca
V
3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca
V
3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of Ca
V
3.1 gene in the inferior olive by
sh
RNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate Ca
V
3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, Ca
V
3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor.
Peak water limits to freshwater withdrawal and use
Authors: Gleick Peter H. , Palaniappan Meena
Published: May 2010

Freshwater resources are fundamental for maintaining human health, agricultural production, economic activity as well as critical ecosystem functions. As populations and economies grow, new constraints on water resources are appearing, raising questions about limits to water availability. Such resource questions are not new. The specter of “peak oil”—a peaking and then decline in oil production—has long been predicted and debated. We present here a detailed assessment and definition of three concepts of “peak water”: peak renewable water, peak nonrenewable water, and peak ecological water. These concepts can help hydrologists, water managers, policy makers, and the public understand and manage different water systems more effectively and sustainably. Peak renewable water applies where flow constraints limit total water availability over time. Peak nonrenewable water is observable in groundwater systems where production rates substantially exceed natural recharge rates and where overpumping or contamination leads to a peak of production followed by a decline, similar to more traditional peak-oil curves. Peak “ecological” water is defined as the point beyond which the total costs of ecological disruptions and damages exceed the total value provided by human use of that water. Despite uncertainties in quantifying many of these costs and benefits in consistent ways, more and more watersheds appear to have already passed the point of peak water. Applying these concepts can help shift the way freshwater resources are managed toward more productive, equitable, efficient, and sustainable use.
Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells
Authors: Delgado Tracie , Carroll Patrick A. , Punjabi Almira S. , Margineantu Daciana , Hockenbery David M. , Lagunoff Michael
Published: May 2010

Kaposi’s sarcoma (KS) is the most commonly reported tumor in parts of Africa and is the most common tumor of AIDS patients world-wide. KS-associated herpesvirus (KSHV) is the etiologic agent of KS. Although KS tumors contain many cell types, the predominant cell is the spindle cell, a cell of endothelial origin that maintains KSHV latency. KSHV activates many cell-signaling pathways but little is known about how KSHV alters cellular metabolism during latency. The Warburg effect, a common metabolic alteration of most tumor cells, is defined by an increase in aerobic glycolysis and a decrease in oxidative phosphorylation as an energy source. The Warburg effect adapts cells to tumor environments and is necessary for the survival of tumor cells. During latent infection of endothelial cells, KSHV induces aerobic glycolysis and lactic acid production while decreasing oxygen consumption, thereby inducing the Warburg effect. Inhibitors of glycolysis selectively induce apoptosis in KSHV-infected endothelial cells but not their uninfected counterparts. Therefore, similar to cancer cells, the Warburg effect is necessary for maintaining KSHV latently infected cells. We propose that KSHV induction of the Warburg effect adapts infected cells to tumor microenvironments, aiding the seeding of KS tumors. Additionally, inhibitors of glycolysis may provide a unique treatment strategy for latent KSHV infection and ultimately KS tumors.
Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms
Authors: An Mahru C. , Lin Weichun , Yang Jiefei , Dominguez Bertha , Padgett Daniel , Sugiura Yoshie , Aryal Prafulla , Gould Thomas W. , Oppenheim Ronald W. , Hester Mark E. , Kaspar Brian K. , Ko Chien-Ping , Lee Kuo-Fen
Published: May 2010

Emerging evidence suggests that the neurotransmitter acetylcholine (ACh) negatively regulates the development of the neuromuscular junction, but it is not clear if ACh exerts its effects exclusively through muscle ACh receptors (AChRs). Here, we used genetic methods to remove AChRs selectively from muscle. Similar to the effects of blocking ACh biosynthesis, eliminating postsynaptic AChRs increased motor axon branching and expanded innervation territory, suggesting that ACh negatively regulates synaptic growth through postsynaptic AChRs. However, in contrast to the effects of blocking ACh biosynthesis, eliminating postsynaptic AChRs in agrin-deficient mice failed to restore deficits in pre- and postsynaptic differentiation, suggesting that ACh negatively regulates synaptic differentiation through nonpostsynaptic receptors. Consistent with this idea, the ACh agonist carbachol inhibited presynaptic specialization of motorneurons in vitro. Together, these data suggest that ACh negatively regulates axon growth and presynaptic specialization at the neuromuscular junction through distinct cellular mechanisms.
Mouse and zebrafish Hoxa3 orthologues have nonequivalent in vivo protein function
Authors: Chen Lizhen , Zhao Peng , Wells Lance , Amemiya Chris T. , Condie Brian G. , Manley Nancy R.
Published: May 2010

Hox
genes play evolutionarily conserved roles in specifying axial position during embryogenesis. A prevailing paradigm is that changes in
Hox
gene expression drive evolution of metazoan body plans. Conservation of Hox function across species, and among paralogous
Hox
genes within a species, supports a model of functional equivalence. In this report, we demonstrate that zebrafish
hoxa3a
(
zfhoxa3a
) expressed from the mouse
Hoxa3
locus can substitute for mouse Hoxa3 in some tissues, but has distinct or null phenotypes in others. We further show, by using an allele encoding a chimeric protein, that this difference maps primarily to the zfhoxa3a C-terminal domain. Our data imply that the mouse and zebrafish proteins have diverged considerably since their last common ancestor, and that the major difference between them resides in the C-terminal domain. Our data further show that Hox protein function can evolve independently in different cell types or for specific functions. The inability of zfhoxa3a to perform all of the normal roles of mouse Hoxa3 illustrates that Hox orthologues are not always functionally interchangeable.
Regulation of a heterodimeric kinesin-2 through an unprocessive motor domain that is turned processive by its partner
Authors: Brunnbauer Melanie , Mueller-Planitz Felix , Kösem Süleyman , Ho Thi Hieu , Dombi Renate , Gebhardt J. Christof M. , Rief Matthias , Ökten Zeynep
Published: May 2010

Cilia are microtubule-based protrusions of the plasma membrane found on most eukaryotic cells. Their assembly is mediated through the conserved intraflagellar transport mechanism. One class of motor proteins involved in intraflagellar transport, kinesin-2, is unique among kinesin motors in that some of its members are composed of two distinct polypeptides. However, the biological reason for heterodimerization has remained elusive. Here we provide several interdependent reasons for the heterodimerization of the kinesin-2 motor KLP11/KLP20 of
Caenorhabditis elegans
cilia. One motor domain is unprocessive as a homodimer, but heterodimerization with a processive partner generates processivity. The “unprocessive” subunit is kept in this partnership as it mediates an asymmetric autoregulation of the motor activity. Finally, heterodimerization is necessary to bind KAP1, the in vivo link between motor and cargo.
Generating sparse and selective third-order responses in the olfactory system of the fly
Authors: Luo Sean X. , Axel Richard , Abbott L. F.
Published: May 2010

In the antennal lobe of
Drosophila
, information about odors is transferred from olfactory receptor neurons (ORNs) to projection neurons (PNs), which then send axons to neurons in the lateral horn of the protocerebrum (LHNs) and to Kenyon cells (KCs) in the mushroom body. The transformation from ORN to PN responses can be described by a normalization model similar to what has been used in modeling visually responsive neurons. We study the implications of this transformation for the generation of LHN and KC responses under the hypothesis that LHN responses are highly selective and therefore suitable for driving innate behaviors, whereas KCs provide a more general sparse representation of odors suitable for forming learned behavioral associations. Our results indicate that the transformation from ORN to PN firing rates in the antennal lobe equalizes the magnitudes of and decorrelates responses to different odors through feedforward nonlinearities and lateral suppression within the circuitry of the antennal lobe, and we study how these two components affect LHN and KC responses.
H
2
S mediates O
2
sensing in the carotid body
Authors: Peng Ying-Jie , Nanduri Jayasri , Raghuraman Gayatri , Souvannakitti Dangjai , Gadalla Moataz M. , Kumar Ganesh K. , Snyder Solomon H. , Prabhakar Nanduri R.
Published: May 2010

Gaseous messengers, nitric oxide and carbon monoxide, have been implicated in O
2
sensing by the carotid body, a sensory organ that monitors arterial blood O
2
levels and stimulates breathing in response to hypoxia. We now show that hydrogen sulfide (H
2
S) is a physiologic gasotransmitter of the carotid body, enhancing its sensory response to hypoxia. Glomus cells, the site of O
2
sensing in the carotid body, express cystathionine γ-lyase (CSE), an H
2
S-generating enzyme, with hypoxia increasing H
2
S generation in a stimulus-dependent manner. Mice with genetic deletion of CSE display severely impaired carotid body response and ventilatory stimulation to hypoxia, as well as a loss of hypoxia-evoked H
2
S generation. Pharmacologic inhibition of CSE elicits a similar phenotype in mice and rats. Hypoxia-evoked H
2
S generation in the carotid body seems to require interaction of CSE with hemeoxygenase-2, which generates carbon monoxide. CSE is also expressed in neonatal adrenal medullary chromaffin cells of rats and mice whose hypoxia-evoked catecholamine secretion is greatly attenuated by CSE inhibitors and in CSE knockout mice.
Regulation of O-glycosylation through Golgi-to-ER relocation of initiation enzymes
Authors: Gill David J. , Chia Joanne , Senewiratne Jamie , Bard Frederic
Published: May 2010

After growth factor stimulation, kinases are activated to regulate multiple aspects of cell physiology. Activated Src is present on Golgi membranes, but its function here remains unclear. We find that Src regulates mucin-type protein O-glycosylation through redistribution of the initiating enzymes, polypeptide N-acetylgalactosaminyl transferases (GalNac-Ts), from the Golgi to the ER. Redistribution occurs after stimulation with EGF or PDGF in a Src-dependent manner and in cells with constitutively elevated Src activity. All GalNac-T family enzymes tested are affected, whereas multiple other glycosylation enzymes are not displaced from the Golgi. Upon Src activation, the COP-I coat is also redistributed in punctate structures that colocalize with GalNac-Ts and a dominant-negative Arf1 isoform, Arf1(Q71L), efficiently blocks GalNac-T redistribution, indicating that Src activates a COP-I–dependent trafficking event. Finally, Src activation increases O-glycosylation initiation as seen by lectin staining and metabolic labeling. We propose that growth factor stimulation regulates O-glycosylation initiation in a Src-dependent fashion by GalNac-T redistribution to the ER.
IL-10 administration reduces PGE-2 levels and promotes CR3-mediated clearance of Escherichia coli K1 by phagocytes in meningitis
Authors: Mittal Rahul , Gonzalez-Gomez Ignacio , Panigrahy Ashok , Goth Kerstin , Bonnet Richard , Prasadarao Nemani V.
Published: May 2010

Ineffectiveness of antibiotics in treating neonatal Escherichia coli K1 meningitis and the emergence of antibiotic-resistant strains evidently warrants new prevention strategies. We observed that administration of interleukin (IL)-10 during high-grade bacteremia clears antibiotic-sensitive and -resistant E. coli from blood of infected mice. Micro-CT studies of brains from infected animals displayed gross morphological changes similar to those observed in infected human neonates. In mice, IL-10, but not antibiotic or anti-TNF antibody treatment prevented brain damage caused by E. coli. IL-10 administration elevated CR3 expression in neutrophils and macrophages of infected mice, whereas infected and untreated mice displayed increased expression of FcγRI and TLR2. Neutrophils or macrophages pretreated with IL-10 ex vivo exhibited a significantly greater microbicidal activity against E. coli compared with cells isolated from wild-type or IL-10−/− mice. The protective effect of IL-10 was abrogated when CR3 was knocked-down in vivo by siRNA. The increased expression of CR3 in phagocytes was caused by inhibition of prostaglandin E-2 (PGE-2) levels, which were significantly increased in neutrophils and macrophages upon E. coli infection. These findings describe a novel modality of IL-10–mediated E. coli clearance by diverting the entry of bacteria via CR3 and preventing PGE-2 formation in neonatal meningitis.
Changes in the Incidences of Multidrug-Resistant and Extensively Drug-Resistant Organisms Isolated in a Military Medical Center
Authors: Keen Edward F. , Murray Clinton K. , Robinson Brian J. , Hospenthal Duane R. , A. Co Edgie-Mark , Aldous Wade K.
Published: May 2010

Background.

Multidrug-resistant (MDR)Acinetobacter baumanniiandPseudomonas aeruginosahave emerged as the causes of nosocomial infections in critically ill patients.

Objective.

To characterize the incidence of these MDR bacteria over time in the military healthcare system, comparing isolates recovered from overseas combat casualties with isolates recovered from local military and civilian patients.

Methods.

Retrospective electronic records review of culture and/or susceptibility testing results of patients admitted to a military level I trauma center in San Antonio, Texas, during the period from January 2001 through December 2008. Multidrug resistance was defined as the first isolated organism resistant to 3 or more classes of antimicrobial agents.

Results.

Over time, the percentage of MDRA. baumanniiisolates increased from 4% to 55%, whereas the percentage of MDRP. aeruginosaisolates increased from 2% to 8%. Respiratory tract specimens had a higher percentage of MDRA. baumanniiisolates (49%), compared with specimens obtained from blood (30%), wound sites (24%), or urine (19%). No difference in the percentages of MDRP. aeruginosaisolates was observed with regard to source of specimen. The percentage of MDRA. baumanniiisolates recovered was higher among patients who had been deployed overseas (52%) than among local patients (20%). When isolates recovered from patients in the burn intensive care unit (53% of MDRA. baumanniiisolates) were removed from analysis, the percentage of MDRA. baumanniiisolates decreased from 38% to 30% while the percentage of MDRP. aeruginosaisolates remained unaffected.

Conclusion.

The percentage of MDRA. baumanniiisolates increased in this facility among combat casualties and among local patients, which indicates nosocomial transmission; however, there was no significant increase in the percentage of MDRP. aeruginosaisolates. Isolated changes in the MDR pathogens within a facility can occur. Possible interventions to limit the spread of these organisms could include implementing aggressive infection control practices, controlling antibiotic use, and using active culture surveillance.
Implications of fisheries-induced changes in stock structure and reproductive potential for stock recovery of a sex-dimorphic species, North Sea plaice
Authors: Rijnsdorp Adriaan D. , van Damme Cindy J. G. , Witthames Peter R.
Published: May 2010

Rijnsdorp, A. D., van Damme, C. J. G., and Witthames, P. R. 2010. Implications of fisheries-induced changes in stock structure and reproductive potential for stock recovery of a sex-dimorphic species, North Sea plaice. – ICES Journal of Marine Science, 67: 1931–1938. A key assumption in stock assessment and stock forecasts often is that spawning-stock biomass (SSB) and egg production are proportional and that the reproductive potential is independent of stock structure (age composition and sex ratio). Based on a 60-year time-series of total egg production (TEP) of North Sea plaice, we demonstrate that this assumption could result in a biased perception of the temporal trend in reproductive potential. The time-series incorporates: (i) annual observations on maturity, growth, and condition, (ii) a predictive model for interannual variations in fecundity caused by variations in body condition and by the probability of being a recruit spawner, and (iii) a cohort analysis of sex-specific landings-at-age since 1948. Following an increase in fishing mortality rate, TEP declined by a factor of 7–8 from a peak in the 1970s to a minimum in 1999–2000. Concurrent with this decline, the contribution of recruit spawners and the size difference between spawning males and females decreased. The implications of phenotypic plasticity and fisheries-induced evolutionary changes in growth and maturation for the recovery potential of the plaice stock are discussed.