bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Arf GTPase-Activating Protein Family Is Exploited by Salmonella enterica Serovar Typhimurium To Invade Nonphagocytic Host Cells
Authors: Davidson Anthony C. , Humphreys Daniel , Brooks Andrew B. E. , Hume Peter J. , Koronakis Vassilis 
Published: February 2015

ABSTRACT
To establish intracellular infections, Salmonella bacteria trigger host cell membrane ruffling and invasion by subverting cellular Arf guanine nucleotide exchange factors (GEFs) that activate Arf1 and Arf6 GTPases by promoting GTP binding. A family of cellular Arf GTPase-activating proteins (GAPs) can downregulate Arf signaling by stimulating GTP hydrolysis, but whether they do this during infection is unknown. Here, we uncovered a remarkable role for distinct Arf GAP family members in Salmonella invasion. The Arf6 GAPs ACAP1 and ADAP1 and the Arf1 GAP ASAP1 localized at Salmonella-induced ruffles, which was not the case for the plasma membrane-localized Arf6 GAPs ARAP3 and GIT1 or the Golgi-associated Arf1 GAP1. Surprisingly, we found that loss of ACAP1, ADAP1, or ASAP1 impaired Salmonella invasion, revealing that GAPs cannot be considered mere terminators of cytoskeleton remodeling. Salmonella invasion was restored in Arf GAP-depleted cells by expressing fast-cycling Arf derivatives, demonstrating that Arf GTP/GDP cycles facilitate Salmonella invasion. Consistent with this view, both constitutively active and dominant-negative Arf derivatives that cannot undergo GTP/GDP cycles inhibited invasion. Furthermore, we demonstrated that Arf GEFs and GAPs colocalize at invading Salmonella and collaborate to drive Arf1-dependent pathogen invasion. This study revealed that Salmonella bacteria exploit a remarkable interplay between Arf GEFs and GAPs to direct cycles of Arf GTPase activation and inactivation. These cycles drive Salmonella cytoskeleton remodeling and enable intracellular infections.

IMPORTANCE
To initiate infections, the Salmonella bacterial pathogen remodels the mammalian actin cytoskeleton and invades host cells by subverting host Arf GEFs that activate Arf1 and Arf6 GTPases. Cellular Arf GAPs deactivate Arf GTPases and negatively regulate cell processes, but whether they target Arfs during infection is unknown. Here, we uncovered an important role for the Arf GAP family in Salmonella invasion. Surprisingly, we found that Arf1 and Arf6 GAPs cooperate with their Arf GEF counterparts to facilitate cycles of Arf GTPase activation and inactivation, which direct pathogen invasion. This report illustrates that GAP proteins promote actin-dependent processes and are not necessarily restricted to negatively regulating cellular signaling. It uncovers a remarkable interplay between Arf GEFs and GAPs that is exploited by Salmonella to establish infection and expands our understanding of Arf GTPase-regulated cytoskeleton remodeling.
Mitochondrial Heat Shock Protein Machinery Hsp70/Hsp40 Is Indispensable for Proper Mitochondrial DNA Maintenance and Replication
Authors: Týč Jiří , Klingbeil Michele M. , Lukeš Julius 
Published: February 2015

ABSTRACT

Mitochondrial chaperones have multiple functions that are essential for proper functioning of mitochondria. In the human-pathogenic protist
Trypanosoma brucei
, we demonstrate a novel function of the highly conserved machinery composed of mitochondrial heat shock proteins 70 and 40 (mtHsp70/mtHsp40) and the ATP exchange factor Mge1. The mitochondrial DNA of T. brucei, also known as kinetoplast DNA (kDNA), is represented by a single catenated network composed of thousands of minicircles and dozens of maxicircles packed into an electron-dense kDNA disk. The chaperones mtHsp70 and mtHsp40 and their cofactor Mge1 are uniformly distributed throughout the single mitochondrial network and are all essential for the parasite. Following RNA interference (RNAi)-mediated depletion of each of these proteins, the kDNA network shrinks and eventually disappears. Ultrastructural analysis of cells depleted for mtHsp70 or mtHsp40 revealed that the otherwise compact kDNA network becomes severely compromised, a consequence of decreased maxicircle and minicircle copy numbers. Moreover, we show that the replication of minicircles is impaired, although the lack of these proteins has a bigger impact on the less abundant maxicircles. We provide additional evidence that these chaperones are indispensable for the maintenance and replication of kDNA, in addition to their already known functions in Fe-S cluster synthesis and protein import.

IMPORTANCE
Impairment or loss of mitochondrial DNA is associated with mitochondrial dysfunction and a wide range of neural, muscular, and other diseases. We present the first evidence showing that the entire mtHsp70/mtHsp40 machinery plays an important role in mitochondrial DNA replication and maintenance, a function likely retained from prokaryotes. These abundant, ubiquitous, and multifunctional chaperones share phenotypes with enzymes engaged in the initial stages of replication of the mitochondrial DNA in T. brucei.
Cost Effectiveness of Using Moxibustion to Correct Non-Vertex Presentation
Authors: García-Mochón Leticia , Martín José J , Aranda-Regules José Manuel , Rivas-Ruiz Francisco , Vas Jorge 
Published: February 2015

Aims To analyse the cost effectiveness of using the moxibustion technique to correct non-vertex presentation and to reduce the number of caesarean sections performed at term. Method A deterministic model of decision analysis has been developed to analyse the cost of treatment in which heat is applied by moxibustion (the combustion of Artemisia vulgaris) at acupuncture point BL67 for pregnant women with non-vertex fetal position at 33–35 weeks’ gestation. This approach was compared with conventional treatment recommendations based on the knee-chest posture technique. The costs were obtained mainly from data provided by the Andalusian Public Health System. Effectiveness data for the baseline analysis were taken from a previous clinical study. A secondary analysis was performed based on a meta-analysis conducted using random effects analysis, by reference to studies published in recent systematic reviews of moxibustion versus conventional treatment, in order to make the results generalisable to other healthcare settings. Deterministic and probabilistic sensitivity analyses were performed under diverse assumptions to assess the uncertainty of the result. Results The baseline analysis shows that the application of moxibustion prevents 8.92% of deliveries with non-vertex presentation compared with conventional treatment, with an average cost saving of ¢107.11 per delivery, mainly due to the cost saving from avoiding the need for caesarean section. The meta-analysis revealed a relative risk of the version of non-vertex presentation at term of 0.34 (95% CI 0.16 to 0.76). The sensitivity analysis showed that moxibustion can avoid 0.34 caesarean sections, with an incremental cost per delivery ranging from ¢68 to −¢640 for moxibustion versus conventional treatment. Conclusions Moxibustion treatment applied at acupuncture point BL67 can avoid the need for caesarean section and achieve cost savings for the healthcare system in comparison with conventional treatment.
Dietary protein-to-carbohydrate ratio and added sugar as determinants of excessive gestational weight gain: a prospective cohort study
Authors: Maslova Ekaterina , Halldorsson Thorhallur I , Astrup Arne , Olsen Sjurdur F 
Published: February 2015

ObjectiveTo examine the relation between the protein:carbohydrate (P/C) ratio and added sugar intake in pregnancy and gestational weight gain (GWG).DesignA prebirth cohort including 103 119 pregnancies enrolled between 1996 and 2003.SettingAll women in Denmark were eligible to participate if they spoke Danish and were planning to carry to term.The pregnant women were recruited and enrolled during their first antenatal visit (6–10 weeks of gestation).ParticipantsParticipants included women with live-born singletons and complete data on dietary intake and GWG, leaving 46 262 women for the analysis.ExposureMacronutrient intake was quantified using a validated food frequency questionnaire administered in the 25th week of gestation. The P/C ratio and added sugar intake were examined in quintiles.Primary outcome measuresGWG was based on self-reported weight in gestational weeks 12 and 30 and defined as gain in g/week. We used multivariable linear regression, including adjusting for pre-pregnancy body mass index, to calculate relative change in GWG and 95% CI.ResultsAverage GWG was 471(224) g/week. The adjusted weight gain was 16 g/week lower (95% CI 9 to 22, p for trend <0.001) in the highest (Q5) versus lowest (Q1) quintile of the P/C ratio (∼3% average reduction across the entire pregnancy). Weight gain for those with >20%E vs <12%E from protein was 36 g/week lower (95% CI 20 to 53, p for trend <0.0001; ∼8% average reduction). A high P/C ratio was inversely related to intake of added sugars. Added sugar consumption was strongly associated with GWG (Q5 vs Q1: 34, 95% CI 28 to 40 g/week, p for trend <0.0001).ConclusionsA high P/C ratio was associated with reduced GWG. This association appeared to be partly driven by a decrease in intake of added sugar. These results are consistent with randomised trials in non-pregnant participants. A dietary intervention targeting an increased P/C ratio with emphasis on reducing added sugar can contribute to reducing excessive GWG.
Validity of a PCI Bleeding Risk Score in patient subsets stratified for body mass index
Authors: Dobies David R , Barber Kimberly R , Cohoon Amanda L 
Published: February 2015

ObjectiveAn accurate tool with good discriminative for bleeding would be useful to clinicians for improved management of all their patients. Bleeding risk models have been published but not externally validated in independent clinical data set. We chose the National Cardiovascular Data Registry (NCDR) percutaneous coronary intervention (PCI) score to validate within a large, multisite community data set. The aim of the study was validation of this Bleeding Risk Score (BRS) tool among a subgroup of patients based on body mass index.MethodsThis is a large-scale retrospective analysis of a current registry utilising data from a 37-hospital health system. The central repository of patients with coronary heart disease undergoing PCI between 1 June 2009 and 30 June 2012 was utilised to validate the NCDR PCI BRS among 4693 patients. The primary end point was major bleeding. Validation analysis calculating the receiver operating characteristic curve was performed.ResultsThere were 143 (3%) major bleeds. Mean BRS was 14.7 (range 3–42). Incidence of bleeding by risk category: low (0.5%), intermediate (1.7%) and high risk (7.6%). Tool accuracy was poor to fair (area-under-the curve (AUC) 0.78 heparin, 0.65 bivalirudin). Overall accuracy was 0.71 (CI 0.66 to 0.76). Accuracy did not improve when confined to just the intermediate risk group (AUC 0.58; CI 0.55 to 0.67). Tool accuracy was the lowest among the low BMI group (AUC 0.62) though they are at increased risk of bleeding following PCI.ConclusionsBleeding risk tools have low predictive value even among subgroups of patients at higher risk. Adjustment for anticoagulation use resulted in poor discrimination because bivalirudin differentially biases outcomes toward no bleeding. The current state of bleeding risk tools provide little support for diagnostic utility in regards to major bleeding and therefore have limited clinical applicability.
CLK2 Is an Oncogenic Kinase and Splicing Regulator in Breast Cancer
Authors: Yoshida Taku , Kim Jee Hyun , Carver Kristopher , Su Ying , Weremowicz Stanislawa , Mulvey Laura , Yamamoto Shoji , Brennan Cameron , Mei Shenglin , Long Henry , Yao Jun , Polyak Kornelia 
Published: February 2015

Abstract
Genetically activated kinases have been attractive therapeutic targets in cancer due to the relative ease of developing tumor-specific treatment strategies for them. To discover novel putative oncogenic kinases, we identified 26 genes commonly amplified and overexpressed in breast cancer and subjected them to a lentiviral shRNA cell viability screen in a panel of breast cancer cell lines. Here, we report that CLK2, a kinase that phosphorylates SR proteins involved in splicing, acts as an oncogene in breast cancer. Deregulated alternative splicing patterns are commonly observed in human cancers but the underlying mechanisms and functional relevance are still largely unknown. CLK2 is amplified and overexpressed in a significant fraction of breast tumors. Downregulation of CLK2 inhibits breast cancer growth in cell culture and in xenograft models and it enhances cell migration and invasion. Loss of CLK2 in luminal breast cancer cells leads to the upregulation of epithelial-to-mesenchymal transition (EMT)-related genes and a switch to mesenchymal splice variants of several genes, including ENAH (MENA). These results imply that therapeutic targeting of CLK2 may be used to modulate EMT splicing patterns and to inhibit breast tumor growth. Cancer Res; 75(7); 1516–26. ©2015 AACR.
Loss of Secreted Frizzled-Related Protein-1 Leads to Deterioration of Cardiac Function in Mice and Plays a Role in Human Cardiomyopathy
Authors: Sklepkiewicz Piotr , Shiomi Takayuki , Kaur Rajbir , Sun Jie , Kwon Susan , Mercer Becky , Bodine Peter , Schermuly Ralph Theo , George Isaac , Schulze P. Christian , D’Armiento Jeanine M. 
Published: February 2015

Background—
The Wnt/β-catenin signaling pathway plays a central role during cardiac development and has been implicated in cardiac remodeling and aging. However, the role of Wnt modulators in this process is unknown. In this study, we examined the role of the Wnt signaling inhibitor secreted frizzled-related protein-1 (sFRP-1) in aged wild-type and sFRP-1–deficient mice.

Methods and Results—
sFRP-1 gene deletion mice were grossly normal with no difference in mortality but developed abnormal cardiac structure and dysfunction with progressive age. Ventricular dilation and hypertrophy in addition to deterioration of cardiac function and massive cardiac fibrosis, all features present in dilated cardiomyopathy, were observed in the aged sFRP-1 knockout mice. Loss of sFRP-1 led to increased expression of Wnt ligands (Wnt1, 3, 7b, and 16) and Wnt target genes (Wisp1 and Lef1) in aged hearts, which correlated with increased protein levels of β-catenin. Cardiac fibroblasts lacking endogenous sFRP-1 showed increased α-smooth muscle actin expression, higher cell proliferation rates, and increased collagen production consistent with the cardiac phenotype exhibited in aged sFRP-1 knockout mice. The clinical relevance of these findings was supported by the demonstration of decreased sFRP-1 gene expression and increased Wisp-1 levels in the left ventricles of patients with ischemic dilated cardiomyopathy and dilated cardiomyopathy.

Conclusions—
This study identifies a novel role of sFRP-1 in age-related cardiac deterioration and fibrosis. Further exploration of this pathway will identify downstream molecules important in these processes and also suggest the potential use of Wnt signaling agents as therapeutic targets for age-related cardiovascular disorders in humans.
Influence of Patient Goals of Care on Performance Measures in Patients Hospitalized for Heart Failure
Authors: McAlister Finlay A. , Wang Julie , Donovan Linda , Lee Douglas S. , Armstrong Paul W. , Tu Jack V. 
Published: February 2015

Background—
Pay for performance programs compare metrics that are risk-adjusted, but goals of care are not considered in current models. We conducted this study to explore the associations between do not resuscitate (DNR) designations, quality of care, and outcomes.

Methods and Results—
Retrospective cohort study with chart review for inpatient quality metrics, 30 day mortality, and readmissions or death within 30 days of discharge in 96 Ontario hospitals participating in the Enhanced Feedback For Effective Cardiac Treatment (EFFECT) study in 2004/05. Of 8339 patients (mean age 77 years) with new heart failure, 1220 (15%) had DNR documented at admission (admission DNR, varying from 0% to 36% between hospitals) and 892 (11%) were switched from full resuscitation to DNR during their index hospitalization (later DNR). Death at 30 days was more common in patients with admission DNR (27%) or later DNR (35%) than full resuscitation (3%)—admission DNR was a stronger predictor (adjusted OR 8.6, 95% confidence interval 6.8–10.7) than any of the variables currently included in heart failure 30 day mortality risk models. Hospital-level rankings differed considerably if DNR patients were excluded: 22 of the 39 EFFECT hospitals in the top and bottom quintiles for 30 day mortality rates (the usual thresholds for rewards/penalties in current performance-based reimbursement schemes) would not have been in those same quintiles if admission DNR patients were excluded.

Conclusions—
Alternate goals of care are frequent and important confounders in heart failure comparative studies. Philosophy of care discussions should be considered for inclusion as a potential quality of care indicator.
Dietary Cysteine and Other Amino Acids and Stroke Incidence in Women
Authors: Larsson Susanna C. , Håkansson Niclas , Wolk Alicja 
Published: February 2015

Background and Purpose—
Cysteine could potentially lower the risk of stroke through antihypertensive and antioxidant effects. Our aim was to evaluate the hypothesis that cysteine intake is inversely associated with stroke incidence.

Methods—
We used data from the Swedish Mammography Cohort, a population-based prospective cohort of 34 250 women who were free of cardiovascular disease and cancer and had completed a food-frequency questionnaire about diet and other risk factors for stroke in the autumn of 1997. Stroke cases were identified by linkage of the study population with the Swedish Inpatient Register and the Swedish Cause of Death Register. Relative risks (RR) with 95% confidence intervals, adjusted for potential confounders, were estimated by using Cox proportional hazards regression model.

Results—

We ascertained 1751 incident cases of stroke during 10.4 years of follow-up. Dietary cysteine intake (mean, 635 mg/d) was inversely associated with stroke risk. The multivariable RR of total stroke comparing the highest with the lowest quintile of cysteine intake was 0.79 (95% confidence interval, 0.65–0.97;
P
for trend=0.04). The corresponding RR was 0.82 (95% confidence interval, 0.65–1.03;
P
for trend=0.12) for cerebral infarction and 0.54 (95% confidence interval, 0.29–1.03;
P
for trend=0.08) for intracerebral hemorrhage. Dietary intake of other amino acids showed no independent (after adjustment for cysteine intake) association with stroke risk.

Conclusions—
These findings suggest that dietary cysteine intake may be inversely associated with risk of stroke.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01127698.
Why do wild bonobos not use tools like chimpanzees do?
Authors: Furuichi T. , Sanz C. , Koops K. , Sakamaki T. , Ryu H. , Tokuyama N. , Morgan D. 
Published: February 2015

One of the most conspicuous behavioural differences among great apes is the paucity of tool use among wild bonobos (Pan paniscus) in comparison to chimpanzees (Pan troglodytes) who are one of the most prolific and skilled tool users in the animal kingdom. This is in spite of the fact that bonobo tool use repertories are as large and diverse as chimpanzees’ in captive settings. In this study, we compared tool using behaviours and potential drivers of these behaviours in the Wamba bonobo population located in central Democratic Republic of Congo with the Goualougo chimpanzee population of northern Republic of Congo. The tool use repertoire of wild bonobos was comprised of only 13 behaviours, compared to 42 for chimpanzees. However, the number of tool behaviours observed in each study site was similar between bonobos and chimpanzees, and many types of tool use for social, self-grooming/stimulation, and comfort/protection functions were commonly used by both species. A marked difference is that 25 of 42 tool behaviours exhibited by chimpanzees are performed for feeding, in contrast to a single report of bonobos using a leaf sponge to drink water. We examined whether the differences in tool use repertoires can be explained by the necessity, opportunity, relative profitability, or invention hypotheses. We found that habitat composition and fluctuation of fruit production at these two sites were similar, particularly when compared with variation observed between sites within each species. Thus it was unlikely that the necessity hypothesis explains the lack of tool use for feeding in bonobos. Though further study at Wamba is needed, we did not identify any obvious differences in prey availability that would indicate differences in tool using opportunities between the sites. This study could not test the relative profitability hypothesis, and further research is needed on whether tool use is the most efficient means of calorie or protein intake for wild apes. Bonobos at Wamba formed much larger and stable parties than chimpanzees at Goualougo, which was contrary to the prediction by the invention hypothesis. Another explanation is that differences in tool use behaviour between bonobos and chimpanzees might not be explained by the current ecological or social conditions, but rather by circumstances during the Pleistocene Epoch. The observed species differences might also reflect divergent behavioural predispositions, rather than actual differences in cognitive abilities.
Of Sound Mind? Dementia and Aspects of Assessing Legal Capacity
Authors: Mäki-Petäjä-Leinonen Anna , Juva Kati 
Published: February 2015

Abstract
As dementia progresses, it weakens a person’s legal capacity. Both legal and medical aspects are closely intertwined in the assessment of legal capacity. It is a legal problem whose solution requires medical expertise and a medical point of view. It is essential for lawyers to have basic knowledge about the effects of dementing illnesses in order to properly understand medical evidence presented in a case. For a physician it is necessary to have knowledge about different kinds of legal capacities and the complexity of legal assessment.
Elucidating taxonomic problems of the genus Disparia Nagano, 1916 of Taiwan and its neighboring areas, with description of one new species (Lepidoptera, Notodontidae)
Authors: WU SHIPHER 
Published: February 2015

The taxonomic problems of the genus Disparia Nagano, 1916 in Taiwan and its neighboring areas are elucidated in the present study. The hitherto well-known separated taxonomic units, Fentonia nigrofasciata Wileman, 1910 and Pseudofentonia medioalbida Nakamura, 1973, are confirmed as the conspecific species based on the type material examination. The latter is here treated as a junior synonym (syn. nov.). The taxon previously identified as “D. nigrofasciata” in most of studies is actually D. wilemani Matsumura, 1925 stat. rev. Fentonia variegata Wileman, 1910 is retained for the eastern Asian population as a subspecies of widespread D. diluta (Wileman, 1910) through comparison with other populations. In addition, one new species, D. kobayashii sp. nov., endemic to Taiwan is described. Including D. maculata (Moore, 1879), totally five Disparia species are distributed in Taiwan.