bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Haemophilus ducreyi LspA1 Protein Inhibits Phagocytosis By Using a New Mechanism Involving Activation of C-Terminal Src Kinase
Authors: Dodd Dana A. , Worth Randall G. , Rosen Michael K. , Grinstein Sergio , van Oers Nicolai S. C. , Hansen Eric J. 
Published: May 2014

ABSTRACT

Haemophilus ducreyi
causes chancroid, a sexually transmitted infection. A primary means by which this pathogen causes disease involves eluding phagocytosis; however, the molecular basis for this escape mechanism has been poorly understood. Here, we report that the LspA virulence factors of
H. ducreyi
inhibit phagocytosis by stimulating the catalytic activity of C-terminal Src kinase (Csk), which itself inhibits Src family protein tyrosine kinases (SFKs) that promote phagocytosis. Inhibitory activity could be localized to a 37-kDa domain (designated YL2) of the 456-kDa LspA1 protein. The YL2 domain impaired ingestion of IgG-opsonized targets and decreased levels of active SFKs when expressed in mammalian cells. YL2 contains tyrosine residues in two EPIYG motifs that are phosphorylated in mammalian cells. These tyrosine residues were essential for YL2-based inhibition of phagocytosis. Csk was identified as the predominant mammalian protein interacting with YL2, and a dominant-negative Csk rescued phagocytosis in the presence of YL2. Purified Csk phosphorylated the tyrosines in the YL2 EPIYG motifs. Phosphorylated YL2 increased Csk catalytic activity, resulting in positive feedback, such that YL2 can be phosphorylated by the same kinase that it activates. Finally, we found that the
Helicobacter pylori
CagA protein also inhibited phagocytosis in a Csk-dependent manner, raising the possibility that this may be a general mechanism among diverse bacteria. Harnessing Csk to subvert the Fcγ receptor (FcγR)-mediated phagocytic pathway represents a new bacterial mechanism for circumventing a crucial component of the innate immune response and may potentially affect other SFK-involved cellular pathways.

IMPORTANCE
Phagocytosis is a critical component of the immune system that enables pathogens to be contained and cleared. A number of bacterial pathogens have developed specific strategies to either physically evade phagocytosis or block the intracellular signaling required for phagocytic activity.
Haemophilus ducreyi
, a sexually transmitted pathogen, secretes a 4,153-amino-acid (aa) protein (LspA1) that effectively inhibits FcγR-mediated phagocytic activity. In this study, we show that a 294-aa domain within this bacterial protein binds to C-terminal Src kinase (Csk) and stimulates its catalytic activity, resulting in a significant attenuation of Src kinase activity and consequent inhibition of phagocytosis. The ability to inhibit phagocytosis via Csk is not unique to
H. ducreyi
, because we found that the
Helicobacter pylori
CagA protein also inhibits phagocytosis in a Csk-dependent manner. Harnessing Csk to subvert the FcγR-mediated phagocytic pathway represents a new bacterial effector mechanism for circumventing the innate immune response.
A protocol for a randomised, double-blind, placebo-controlled study of the effect of LIraglutide on left VEntricular function in chronic heart failure patients with and without type 2 diabetes (The LIVE Study)
Authors: Jorsal Anders , Wiggers Henrik , Holmager Pernille , Nilsson Brian , Nielsen Roni , Boesgaard Trine Welløv , Kumme Anja , Møller Jacob Eifer , Videbæk Lars , Kistorp Caroline , Gustafsson Ida , Tarnow Lise , Flyvbjerg Allan 
Published: May 2014

IntroductionHeart failure is one of the most common cardiovascular complications of diabetes and the most disabling and deadly complication too. Many antidiabetic agents have been associated with increased morbidity and mortality in a subset of patients with chronic heart failure (CHF); thus, new treatment modalities are warranted. Interestingly, a beneficial effect of the incretin hormone, GLP-1, on cardiac function has been suggested in patients with diabetes and patients without diabetes. Liraglutide (Victoza) is a GLP-1 analogue developed for the treatment of type 2 diabetes (T2D); however, its impact on cardiac function has not previously been investigated in patients with CHF. This prompted us to investigate whether liraglutide treatment for 24 weeks improves left ventricular ejection fraction (LVEF) in patients with CHF with and without T2D compared with placebo treatment.Methods and analysisAn investigator-initiated, multicentre, randomised, double-blind, parallel, placebo-controlled intervention trial. In total, 240 patients with CHF (with and without T2D) with LVEF≤45% will be randomised to either subcutaneous injection of liraglutide 1.8 mg or matching placebo once daily for 24 weeks. The effect of liraglutide on left ventricular function will be evaluated by advanced echocardiography, including three-dimensional contrast echocardiography.Ethics and disseminationThe study will be performed and monitored according to the Good Clinical Practice-International Conference on Harmonisation (GCP-ICH) regulations and conducted according to the principles of the Helsinki Declaration. The Danish Medicines Agency, the local Research Ethics Committee and the Danish Data Protection Agency have approved the study.Trial registration numberClinicalTrials.gov Identifier:NCT01472640.
Impact of the 2011 Great East Japan Earthquake on community health: ecological time series on transient increase in indirect mortality and recovery of health and long-term-care system
Authors: Uchimura Mari , Kizuki Masashi , Takano Takehito , Morita Ayako , Seino Kaoruko 
Published: May 2014

BackgroundThe objectives were to clarify the trend in the cause-specific mortality rate and changes in health and long-term-care use after the Great East Japan Earthquake in 2011.MethodsWe obtained the following data from national sources: the number of deaths by cause, age and month; the amount of healthcare insurance expenditures by type of services, age and month; the amount of long-term-care insurance expenditures by type of services, age, care need and month. We estimated increase in standardised mortality rate postearthquake compared with pre-earthquake, and change in the standardised amount of health and long-term-care insurance expenditures post-earthquake compared with pre-earthquake in three severely affected prefectures, Iwate, Miyagi and Fukushima, by the adjustment for trends in the other prefectures.ResultsThe risk of indirect mortality increased in the month of the earthquake (relative risk (RR) with 95% CI 1.20 (1.13 to 1.28) for those 60–69 years of age, 1.25 (1.17 to 1.32) for 70–79 years, and 1.33 (1.27 to 1.38) for 80 years and older). The amount of health and long-term-care insurance expenditures decreased among elderly persons in the month of the earthquake, and recovered to 95% of usual level within 1–5 months. Among cities and towns hit by tsunami, higher percentage of households flooded was associated with higher risk of indirect mortality (p<0.001), lower expenditures for outpatient medical care (p<0.001), and lower expenditures for home-care services (p<0.001).ConclusionsThis study showed transient increase in indirect mortality and recovery of health and long-term-care system after the earthquake.
Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells
Authors: Dragoi Ana-Maria , Swiss Rachel , Gao Beile , Agaisse Hervé 
Published: May 2014

AbstractE-cadherin downregulation in cancer cells is associated with epithelial-to-mesenchymal transition (EMT) and metastatic prowess, but the underlying mechanisms are incompletely characterized. In this study, we probed E-cadherin expression at the plasma membrane as a functional assay to identify genes involved in E-cadherin downregulation. The assay was based on the E-cadherin–dependent invasion properties of the intracellular pathogen Listeria monocytogenes. On the basis of a functional readout, automated microscopy and computer-assisted image analysis were used to screen siRNAs targeting 7,000 human genes. The validity of the screen was supported by its definition of several known regulators of E-cadherin expression, including ZEB1, HDAC1, and MMP14. We identified three new regulators (FLASH, CASP7, and PCGF1), the silencing of which was sufficient to restore high levels of E-cadherin transcription. In addition, we identified two new regulators (FBXL5 and CAV2), the silencing of which was sufficient to increase E-cadherin expression at a posttranscriptional level. FLASH silencing regulated the expression of E-cadherin and other ZEB1-dependent genes, through posttranscriptional regulation of ZEB1, but it also regulated the expression of numerous ZEB1-independent genes with functions predicted to contribute to a restoration of the epithelial phenotype. Finally, we also report the identification of siRNA duplexes that potently restored the epithelial phenotype by mimicking the activity of known and putative microRNAs. Our findings suggest new ways to enforce epithelial phenotypes as a general strategy to treat cancer by blocking invasive and metastatic phenotypes associated with EMT. Cancer Res; 74(14); 3659–72. ©2014 AACR.
(+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38
Authors: Lim Do Young , Lee Mee-Hyun , Shin Seung Ho , Chen Hanyoung , Ryu Joohyun , Shan Lei , Li Honglin , Bode Ann M. , Zhang Wei-Dong , Dong Zigang 
Published: May 2014

Abstract
For decades, skin cancer incidence has increased, mainly because of oncogenic signaling pathways activated by solar ultraviolet (UV) irradiation (i.e., sun exposure). Solar UV induces multiple signaling pathways that are critical in the development of skin cancer, and therefore the development of compounds capable of targeting multiple molecules for chemoprevention of skin carcinogenesis is urgently needed. Herein, we examined the chemopreventive effects and the molecular mechanism of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 Cl41 cells without toxicity. PI3K, ERK1/2, and p38 kinase activities were suppressed by direct binding with HOEC in vitro. Our in silico docking data showed that HOEC binds at the ATP-binding site of each kinase. The inhibition of solar UV-induced PI3K, ERK1/2, and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP1 and NF-κB transactivation in JB6 cells. Furthermore, topical application of HOEC reduced skin cancer incidence and tumor volume in SKH-1 hairless mice chronically exposed to solar UV. In summary, our results show that HOEC exerts inhibitory effects on multiple kinase targets and their downstream pathways activated by solar UV in vitro and in vivo. These findings suggest that HOEC is a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure. Cancer Prev Res; 7(8); 856–65. ©2014 AACR.
Health System Characteristics and Rates of Readmission After Acute Myocardial Infarction in the United States
Authors: Brown Jeremiah R. , Chang Chiang‐Hua , Zhou Weiping , MacKenzie Todd A. , Malenka David J. , Goodman David C. 
Published: May 2014

Background
Interventions to reduce early readmissions have focused on patient characteristics and the importance of early follow‐up; however, less is known about the characteristics of health systems, including quality, capacity, and intensity, and their influence on readmission rates in the United States. Therefore, we examined the association of hospital patterns of medical care with rates of 30‐day readmission.

Methods and Results

Medicare beneficiaries hospitalized for an
AMI
(n=188 611) between 2008 and 2009 in 1088 hospitals in the United States were included in our cohort. We tested the association between hospital patterns of medical care quality (discharge planning care quality), capacity (hospital size measured as the number of beds, hospital‐level Medicare all medical admission rates, supply of primary care physicians and cardiologists), and intensity (measures of care during the last 6 months of life) on
CMS
risk‐adjusted rates of 30‐day readmission using Poisson multilevel mixed‐effects models adjusting for patient‐ and hospital‐level covariates. There were 38 350 readmissions at 30‐days (20.3%)
AMI
discharges. Controlling for patient characteristics, measures of hospital care associated with higher rates of readmission included higher hospital‐level rates for all medical admissions, per capita primary care physicians and cardiologists, and last 6 months of life care intensity measures including increased number of hospital days, number of
ICU
days, number of physician visits, and 10 or more different physicians seen during the last 6 months of life. Better discharge quality and larger hospitals were associated with lower rates of readmission.

Conclusions
In addition to quality of care, high 30‐day readmission rates are associated with hospital‐level measures of capacity and intensity. Efforts to reduce readmission rates may need to address these broader patterns of medical care.
Physical Activity and Exercise Recommendations for Stroke Survivors
Authors: Billinger Sandra A. , Arena Ross , Bernhardt Julie , Eng Janice J. , Franklin Barry A. , Johnson Cheryl Mortag , MacKay-Lyons Marilyn , Macko Richard F. , Mead Gillian E. , Roth Elliot J. , Shaughnessy Marianne , Tang Ada 
Published: May 2014

Purpose—
This scientific statement provides an overview of the evidence on physical activity and exercise recommendations for stroke survivors. Evidence suggests that stroke survivors experience physical deconditioning and lead sedentary lifestyles. Therefore, this updated scientific statement serves as an overall guide for practitioners to gain a better understanding of the benefits of physical activity and recommendations for prescribing exercise for stroke survivors across all stages of recovery.

Methods—
Members of the writing group were appointed by the American Heart Association Stroke Council’s Scientific Statement Oversight Committee and the American Heart Association’s Manuscript Oversight Committee. The writers used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and indicate gaps in current knowledge.

Results—
Physical inactivity after stroke is highly prevalent. The assessed body of evidence clearly supports the use of exercise training (both aerobic and strength training) for stroke survivors. Exercise training improves functional capacity, the ability to perform activities of daily living, and quality of life, and it reduces the risk for subsequent cardiovascular events. Physical activity goals and exercise prescription for stroke survivors need to be customized for the individual to maximize long-term adherence.

Conclusions—
The recommendation from this writing group is that physical activity and exercise prescription should be incorporated into the management of stroke survivors. The promotion of physical activity in stroke survivors should emphasize low- to moderate-intensity aerobic activity, muscle-strengthening activity, reduction of sedentary behavior, and risk management for secondary prevention of stroke.
A MODIS-Based Global 1-km Maximum Green Vegetation Fraction Dataset
Authors: Broxton Patrick D. , Zeng Xubin , Scheftic William , Troch Peter A. 
Published: May 2014

AbstractGlobal land-cover data are widely used in regional and global models because land cover influences land–atmosphere exchanges of water, energy, momentum, and carbon. Many models use data of maximum green vegetation fraction (MGVF) to describe vegetation abundance. MGVF products have been created in the past using different methods, but their validation with ground sites is difficult. Furthermore, uncertainty is introduced because many products use a single year of satellite data. In this study, a global 1-km MGVF product is developed on the basis of a “climatology” of data of Moderate Resolution Imaging Spectroradiometer (MODIS) normalized difference vegetation index and land-cover type, which removes biases associated with unusual greenness and inaccurate land-cover classification for individual years. MGVF shows maximum annual variability from 2001 to 2012 for intermediate values of average MGVF, and the standard deviation of MGVF normalized by its mean value decreases nearly monotonically as MGVF increases. In addition, there are substantial differences between this climatology and MGVF data from the MODIS Continuous Fields (CF) Collection 3, which is currently used in the Community Land Model. Although the CF data only use 2001 MODIS data, many of these differences cannot be explained by usage of different years of data. In particular, MGVF as based on CF data is usually higher than that based on the MODIS climatology from this paper. It is difficult to judge which product is more realistic because of a lack of ground truth, but this new MGVF product is more consistent than the CF data with the MODIS leaf area index product (which is also used to describe vegetation abundance in models).
Idiopathic intracranial hypertension
Authors: Wakerley BR , Tan MH , Ting EY 
Published: May 2014

Background Idiopathic intracranial hypertension or pseudotumour cerebri is primarily a disorder of young obese women characterised by symptoms and signs associated with raised intracranial pressure in the absence of a space-occupying lesion or other identifiable cause. Summary The overall incidence of idiopathic intracranial hypertension is approximately two per 100,000, but is considerably higher among obese individuals and, given the global obesity epidemic, is likely to rise further. The pathophysiology of this condition is poorly understood, but most theories focus on the presence of intracranial venous hypertension and/or increased cerebrospinal fluid outflow resistance and how this relates to obesity. A lack of randomised clinical trials has resulted in unsatisfactory treatment guidelines and although weight loss is important, especially when used in conjunction with drugs that reduce cerebrospinal fluid production, resistant cases remain difficult to manage and patients invariably undergo neurosurgical shunting procedures. The use of transverse cerebral sinus stenting remains contentious and long-term benefits are yet to be determined. Conclusion An understanding of the clinical features, diagnostic work-up and therapeutic options available for patients with idiopathic intracranial hypertension is important both for neurologists and ophthalmologists as visual loss maybe permanent if untreated.
Vestibular migraine
Authors: Stolte Benjamin , Holle Dagny , Naegel Steffen , Diener Hans-Christoph , Obermann Mark 
Published: May 2014

Background The combination of vertigo, dizziness and balance disturbance with migraine is called vestibular migraine. Although it is estimated that up to 1% of the population suffers from this disease, it is still widely unknown and often underdiagnosed. Recently, the International Headache Society and the Báràny Society published the first joint document with mutually accepted diagnostic criteria for vestibular migraine. Method This review summarizes current knowledge on vestibular migraine with regard to epidemiology, clinical presentation, pathophysiology, differential diagnosis and therapeutic options. Results Approximately 30–50% of patients with migraine report vertigo, dizziness or balance disturbances with at least one migraine attack. Vestibular migraine often appears in a temporal delay to the first onset of migraine headache. In some patients the symptom of sudden onset disequilibrium was the main complaint and more worrisome than the accompanying migraine headache. The duration of attacks varies from a few seconds up to few days. The underlying pathophysiology of vestibular migraine is still widely unknown. As an important differential diagnosis, Ménière’s disease has to be considered and excluded. Conclusion As randomized controlled treatment trials are still missing in vestibular migraine, the therapeutic recommendations for vestibular migraine are currently based on the guidelines of migraine.
Mesenchymal stem cells ameliorate diabetic glomerular fibrosis in vivo and in vitro by inhibiting TGF-β signalling via secretion of bone morphogenetic protein 7
Authors: Lv Shasha , Liu Gang , Sun Aili , Wang Jianping , Cheng Jing , Wang Weiwei , Liu Xiangchun , Nie Huibin , Guan Guangju 
Published: May 2014

Purpose: To investigate whether mesenchymal stem cells (MSCs) could inhibit transforming growth factor beta (TGF-β) signalling pathway by paracrine action. Methods: Bone marrow–derived MSCs were transplanted to streptozotocin-induced diabetic rats via tail vein. MSC-conditioned media were used with a model of mesangial cell fibrosis induced by high glucose in vitro. Results: At 8 weeks after MSC treatment, the renal function and the glomerulosclerosis as revealed by periodic acid Schiff stain was dramatically attenuated. The expression of collagen I, collagen IV and α-smooth muscle actin (SMA) in diabetic kidney was decreased, and E-cadherin increased after MSC treatment. The TGF-β signalling pathway was suppressed both in vivo and in vitro. MSCs secreted a significant amount of bone morphogenetic protein 7 (BMP7), in vitro, MSC-conditioned media inhibited TGF-β signalling stimulated by high glucose, and BMP7 neutralizing antibody blocked the inhibitory effect of MSC-conditioned media. Conclusion: MSCs ameliorated glomerular fibrosis in vivo and in vitro by inhibiting TGF-β/Smad signalling pathway via secretion of BMP7.
Defending Puts the Anterior Cruciate Ligament at Risk During Soccer
Authors: Brophy Robert H. , Stepan Jeffrey G. , Silvers Holly J. , Mandelbaum Bert R. 
Published: May 2014

Background: Soccer athletes are at risk for anterior cruciate ligament (ACL) injury. To date, there are limited studies on the mechanisms of ACL injuries in soccer athletes and no video-based analysis or sex-based comparison of these mechanisms. Hypothesis: There is no difference in ACL injury mechanisms among soccer athletes by sex. Study design: Case series. Level of evidence: Level 4. Methods: Fifty-five videos of ACL injuries in 32 male and 23 female soccer players were reviewed. Most athletes were professionals (22 males, 4 females) or collegiate players (8 males, 14 females). Visual analysis of each case was performed to describe the injury mechanisms in detail (game situation, player behavior, and lower extremity alignment). Results: The majority of ACL injuries occurred when the opposing team had the ball and the injured athlete was defending (73%). Females were more likely to be defending when they injured their ACLs (87% vs 63% for males, P = 0.045). The most common playing action was tackling (51%), followed by cutting (15%). Most injuries occurred due to a contact mechanism (56%) with no significant difference for sex. Females were more likely to suffer a noncontact injury in their left knee (54%) than males (33%) ( P = 0.05). Conclusion: Soccer players are at greatest risk for ACL injury when defending, especially when tackling the opponent in an attempt to win possession of the ball. Females are more likely to injure their ACLs when defending and are at greater risk for noncontact injuries in their left lower extremity. Clinical Relevance: Soccer ACL injury prevention programs should include proper defending and tackling techniques, particularly for female athletes.