bluuebunny/crossref_metadata_2025_split huggingface dataset:
Automatic inference of memory fences
Authors: Kuperstein Michael , Vechev Martin , Yahav Eran 
Published: June 2012

We addresses the problem of automatic verification and fence inference in concurrent programs running under relaxed memory models. Modern architectures implement relaxed memory models in which memory operations may be reordered and executed non-atomically. Instructions called
memory fences
are provided to the programmer, allowing control of this behavior. To ensure correctness of many algorithms, the programmer is often required to explicitly insert memory fences into her program. However, she must use as few fences as possible, or the benefits of the relaxed architecture may be lost. It is our goal to help automate the fence insertion process.

We present an algorithm for automatic inference of memory fences in concurrent programs, relieving the programmer from this complex task. Given a finite-state program, a safety specification and a description of the memory model our algorithm computes a set of ordering constraints that guarantee the correctness of the program under the memory model. The computed constraints are maximally permissive: removing any constraint from the solution would permit an execution violating the specification. These constraints are then realized as additional fences in the input program.
We implemented our approach in a pair of tools called fender and blender and used them to infer correct and efficient placements of fences for several non-trivial algorithms, including practical mutual exclusion primitives and concurrent data structures.
Alternate Splicing of the p53 Inhibitor HDMX Offers a Superior Prognostic Biomarker than p53 Mutation in Human Cancer
Authors: Lenos Kristiaan , Grawenda Anna M. , Lodder Kirsten , Kuijjer Marieke L. , Teunisse Amina F.A.S. , Repapi Emmanouela , Grochola Lukasz F. , Bartel Frank , Hogendoorn Pancras C.W. , Wuerl Peter , Taubert Helge , Cleton-Jansen Anne-Marie , Bond Gareth L. , Jochemsen Aart G. 
Published: June 2012

AbstractConventional high-grade osteosarcoma is the most common primary bone malignancy. Although altered expression of the p53 inhibitor HDMX (Mdmx/Mdm4) is associated with cancer risk, progression, and outcome in other tumor types, little is known about its role in osteosarcoma. High expression of the Hdmx splice variant HDMX-S relative to the full-length transcript (the HDMX-S/HDMX-FL ratio) correlates with reduced HDMX protein expression, faster progression, and poorer survival in several cancers. Here, we show that the HDMX-S/HDMX-FL ratio positively correlates with less HDMX protein expression, faster metastatic progression, and a trend to worse overall survival in osteosarcomas. We found that the HDMX-S/HDMX-FL ratio associated with common somatic genetic lesions connected with p53 inhibition, such as p53 mutation and HDM2 overexpression in osteosarcoma cell lines. Interestingly, this finding was not limited to osteosarcomas as we observed similar associations in breast cancer and a variety of other cancer cell lines, as well as in tumors from patients with soft tissue sarcoma. The HDMX-S/HDMX-FL ratio better defined patients with sarcoma with worse survival rates than p53 mutational status. We propose a novel role for alternative splicing of HDMX, whereby it serves as a mechanism by which HDMX protein levels are reduced in cancer cells that have already inhibited p53 activity. Alternative splicing of HDMX could, therefore, serve as a more effective biomarker for p53 pathway attenuation in cancers than p53 gene mutation. Cancer Res; 72(16); 4074–84. ©2012 AACR.
Alveolar Hypoxia Promotes Murine Lung Tumor Growth through a VEGFR-2/EGFR-Dependent Mechanism
Authors: Karoor Vijaya , Le Mysan , Merrick Daniel , Fagan Karen A. , Dempsey Edward C. , Miller York E. 
Published: June 2012

Abstract
Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD. Cancer Prev Res; 5(8); 1061–71. ©2012 AACR.
Endothelial Microparticle Uptake in Target Cells Is Annexin I/Phosphatidylserine Receptor Dependent and Prevents Apoptosis
Authors: Jansen Felix , Yang Xiaoyan , Hoyer Friedrich Felix , Paul Kathrin , Heiermann Nadine , Becher Marc Ulrich , Hussein Nebal Abu , Kebschull Moritz , Bedorf Jörg , Franklin Bernardo S. , Latz Eicke , Nickenig Georg , Werner Nikos 
Published: June 2012

Objective—
Endothelial microparticles (EMP) are released from activated or apoptotic cells, but their effect on target cells and the exact way of incorporation are largely unknown. We sought to determine the uptake mechanism and the biological effect of EMP on endothelial and endothelial-regenerating cells.

Methods and Results—
EMP were generated from starved endothelial cells and isolated by ultracentrifugation. Caspase 3 activity assay and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that EMP protect target endothelial cells against apoptosis in a dose-dependent manner. Proteomic analysis was performed to identify molecules contained in EMP, which might be involved in EMP uptake. Expression of annexin I in EMP was found and confirmed by Western blot, whereas the corresponding receptor phosphatidylserine receptor was present on endothelial target cells. Silencing either annexin I on EMP or phosphatidylserine receptor on target cells using small interfering RNA showed that the uptake of EMP by human coronary artery endothelial cells is annexin I/phosphatidylserine receptor dependent. Annexin I–downregulated EMP abrogated the EMP-mediated protection against apoptosis of endothelial target cells. p38 activation was found to mediate camptothecin-induced apoptosis. Finally, human coronary artery endothelial cells pretreated with EMP inhibited camptothecin-induced p38 activation.

Conclusion—
EMP are incorporated by endothelial cells in an annexin I/phosphatidylserine receptor–dependent manner and protect target cells against apoptosis. Inhibition of p38 activity is involved in EMP-mediated protection against apoptosis.
Outcome After Mobilization Within 24 Hours of Acute Stroke
Authors: Sundseth Antje , Thommessen Bente , Rønning Ole Morten 
Published: June 2012

Background and Purpose—
Very early mobilization (VEM) is considered to contribute to the beneficial effects of stroke units, but there are uncertainties regarding the optimal time to start mobilization. We hypothesized that VEM within 24 hours after admittance to the hospital would reduce poor outcome 3 months poststroke compared with mobilization between 24 and 48 hours.

Methods—
We conducted a prospective, randomized, controlled trial with blinded assessment at follow-up. Patients admitted to the stroke unit within 24 hours after stroke were assigned to either VEM within 24 hours of admittance or mobilization between 24 and 48 hours (control group). Primary outcome was the proportion of poor outcome (modified Rankin scale score, 3–6), whereas secondary outcomes were death rate, change in neurological impairment (National Institutes of Health Stroke Scale score), and dependency (Barthel Index 0–17).

Results—

Fifty-six patients were included (mean age±SD, 76.9±9.4 years), 27 were in the VEM group and 29 were in the control group. VEM patients had nonsignificant higher odds (adjusted for age and National Institutes of Health Stroke Scale score on admission) of poor outcome (OR, 2.70; 95% CI, 0.78–9.34;
P
=0.12), death (OR, 5.26; 95% CI, 0.84–32.88;
P
=0.08), and dependency (OR, 1.25; 95% CI, 0.36–4.34;
P
=0.73). The control group, having milder strokes (National Institutes of Health Stroke Scale score±SD: control group, 7.5±4.2; VEM, 9.2±6.5;
P
=0.26), had better neurological improvement (
P
=0.02).

Conclusions—
We identified a trend toward increased poor outcome, death rate, and dependency among patients mobilized within 24 hours after hospitalization, and an improvement in neurological functioning in favor of patients mobilized between 24 and 48 hours. Very early or delayed mobilization after acute stroke is still undergoing debate, and results from ongoing larger trials are required.
Reperfusion Rather than Ischemia Drives the Formation of Ubiquitin Aggregates After Middle Cerebral Artery Occlusion
Authors: Hochrainer Karin , Jackman Katherine , Anrather Josef , Iadecola Costantino 
Published: June 2012

Background and Purpose—
Cerebral ischemia leads to accumulation of ubiquitinated protein aggregates. However, the factors triggering ubiquitination and their impact on the outcome of cerebral ischemia remain poorly understood. Here we investigate the relationship between ubiquitin aggregation and duration of ischemia/reperfusion, infarct volume, and proteasomal activity in a mouse model of focal ischemia.

Methods—
Free ubiquitin and ubiquitin aggregate levels were examined by Western blotting in the mouse neocortex and striatum after different periods of ischemia/reperfusion and permanent ischemia induced by middle cerebral artery occlusion. Infarct volumes were measured in thionin-stained brain sections. Proteasome activity was studied by fluorometric peptidase activity assay.

Results—
Following transient ischemia, ubiquitin aggregates were detected in the ipsilateral neocortex and, to a lesser extent, striatum only after induction of reperfusion. In permanent ischemia, no ubiquitin aggregates were found. Shorter ischemic periods producing no or minimal tissue damage (10–15 minutes) resulted in ubiquitin aggregate levels similar to those produced by ischemia resulting in substantial infarction (30 minutes). Proteasomal impairment was greatest in ischemia without reperfusion, in which no ubiquitin aggregates were detected.

Conclusions—
The data demonstrate that reperfusion rather than ischemia leads to the appearance of ubiquitinated aggregates, which form in the absence of major tissue damage and are not correlated with decreased proteasomal peptidase activity. Ubiquitin aggregates may form in potentially viable brain tissue, which may be later recruited into infarction by factors independent of ubiquitination.
Declining Stroke and Myocardial Infarction Mortality Between 1989 and 2010 in a Country of the African Region
Authors: Stringhini Silvia , Sinon Flavie , Didon Joaquim , Gedeon Jude , Paccaud Fred , Bovet Pascal 
Published: June 2012

Background and Purpose—
In low- and middle-income countries, the total burden of cardiovascular diseases is expected to increase due to demographic and epidemiological transitions. However, data on cause-specific mortality are lacking in sub-Saharan Africa. Seychelles is one of the few countries in the region where all deaths are registered and medically certified. In this study, we examine trends in mortality for stroke and myocardial infarction (MI) between 1989 and 2010.

Methods—
Based on vital statistics, we ascertained stroke and MI as the cause of death if appearing in any of the 4 fields for immediate, intermediate, underlying, and contributory causes in death certificates.

Results—
Mortality rates (per 100 000, age-standardized to World Health Organization standard population) decreased from 1669/710 (men/women) in 1989 to 1991 to 1113/535 in 2008–10 for all causes, from 250/140 to 141/86 for stroke, and from 117/51 to 59/24 for MI, corresponding to proportionate decreases of 33%/25% for all-cause mortality, 44%/39% for stroke, and 50%/53% for MI over 22 years. The absolute number of stroke and MI deaths did not increase over time. In 2008 to 2010, the median age of death was 65/78 years (men/women) for all causes, 68/78 for stroke, and 66/73 for MI.

Conclusions—
Between 1989 and 2010, age-standardized stroke and MI mortality decreased markedly and more rapidly than all-cause mortality. The absolute number of cardiovascular disease deaths did not increase over time because the impact of population aging was fully compensated by the decline in cardiovascular disease mortality. Stroke mortality remained high, emphasizing the need to strengthen cardiovascular disease prevention and control.
Evidence of Corticospinal Tract Injury at Midbrain in Patients With Subarachnoid Hemorrhage
Authors: Yeo Sang Seok , Choi Byung Yeon , Chang Chul Hoon , Kim Seong Ho , Jung Young-Jin , Jang Sung Ho 
Published: June 2012

Background and Purpose—
Clear elucidation of the exact pathophysiological mechanisms of motor weakness in patients with subarachnoid hemorrhage has not yet been achieved. We attempted to investigate injury to the corticospinal tract in patients with subarachnoid hemorrhage using diffusion tensor imaging.

Methods—
Twenty-two patients with subarachnoid hemorrhage and 24 control subjects were recruited for this study. DTI-Studio software was used for reconstruction of the corticospinal tract. We measured fractional anisotropy and apparent diffusion coefficient values at 5 regions of interest along the corticospinal tract pathway including: the corona radiata, the posterior limb of the internal capsule, the upper midbrain, the midpons, and the upper medulla.

Results—

Fractional anisotropy value for the midbrain region of interest was lower in the patient group compared with the control group without change of apparent diffusion coefficient value (
P
<0.05). By contrast, fractional anisotropy and apparent diffusion coefficient values of the other 4 regions of interest were not different between the patient and control groups.

Conclusions—
Injury of the corticospinal tract at the midbrain was observed in patients with subarachnoid hemorrhage. Injury of the corticospinal tract at the midbrain appears to be one of the various pathophysiological mechanisms for motor weakness after subarachnoid hemorrhage.
Individual work support for employed patients with low back pain: a randomized controlled pilot trial
Authors: Coole Carol , Drummond Avril , Watson Paul J 
Published: June 2012

Objective: To investigate the feasibility and effectiveness of individual work support for employed patients with low back pain. Design: Pilot randomized controlled trial of a 16-week vocational intervention with six-month follow-up. Setting: Community/outpatient. Participants: Fifty-one employed participants concerned about their ability to work due to low back pain. Outcome data was obtained for 38 participants at six-month follow-up. Interventions: The intervention group received up to eight individually targeted vocational sessions in conjunction with group rehabilitation for low back pain. The control group received group rehabilitation. Outcome measures: The feasibility of the intervention was assessed by the recruitment rate, drop-out and loss to follow-up of the participants and the content and delivery of the intervention as recorded by the researcher. The primary outcome measure was perceived work ability. Results: Seventy-three participants were referred to the study over six months. Eighty-seven individual work support sessions were delivered. Thirty-one participants (61% of those retained in the study) attended more than half of the group rehabilitation sessions. The intervention was influenced by the uptake of group rehabilitation, the willingness of the participants to involve their workplace and of their workplace to involve the research therapist. The effect of the intervention on work ability was equivocal. Conclusions: Although it was possible to recruit participants and to deliver the intervention, considerable methodological problems were identified. However, even if these were addressed, the impact of such interventions is likely to be limited unless there is an integrated approach between healthcare, employers and employees. Further research is required to evaluate work-focused interventions with this client group.
Density and compressive strength properties of polyester composites reinforced with spiral geometry woven fiber
Authors: Ateş Ergun , Aztekin Kadir 
Published: June 2012

Composites can be produced by combining different materials according to different targets. In this study, woven-type E-glass fiber with a 500 g/m2 unit-area weight has been used as a reinforcement material. Resin, hardener and accelerator have been used as the matrix materials. The dimensions of compression test sample molds were Ø50 mm × 100 mm. Starting from the center toward the outer diameter, spirally wound fibers have been placed into molds with intervals ranging from 1 mm to 9 mm. Composite materials have been prepared at room temperature by applying vibration to the casting method. Compression tests have been carried out on a total of 27 samples, as 3 samples per dimension. It has been determined that the compressive strengths of the polyester resin composites reinforced with spirally wound fiberglass changes per the spiral geometry. The highest compressive strength and density value have been obtained from the samples prepared with intervals of 1 mm. Compressive strength and density value curves have exhibited similar tendencies.
DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells
Authors: Hosszu Kinga K. , Valentino Alisa , Vinayagasundaram Uma , Vinayagasundaram Rama , Joyce M. Gordon , Ji Yan , Peerschke Ellinor I. B. , Ghebrehiwet Berhane 
Published: June 2012

AbstractC1q modulates the differentiation and function of cells committed to the monocyte-derived dendritic cell (DC) lineage. Because the 2 C1q receptors found on the DC surface—gC1qR and cC1qR—lack a direct conduit into intracellular elements, we postulated that the receptors must form complexes with transmembrane partners. In the present study, we show that DC-SIGN, a C-type lectin expressed on DCs, binds directly to C1q, as assessed by ELISA, flow cytometry, and immunoprecipitation experiments. Surface plasmon resonance analysis revealed that the interaction was specific, and both intact C1q and the globular portion of C1q bound to DC-SIGN. Whereas IgG reduced this binding significantly, the Arg residues (162-163) of the C1q-A chain, which are thought to contribute to the C1q-IgG interaction, were not required for C1q binding to DC-SIGN. Binding was reduced significantly in the absence of Ca2+ and by preincubation of DC-SIGN with mannan, suggesting that C1q binds to DC-SIGN at its principal Ca2+-binding pocket, which has increased affinity for mannose residues. Antigen-capture ELISA and immunofluorescence microscopy revealed that C1q and gC1qR associate with DC-SIGN on blood DC precursors and immature DCs. The results of the present study suggest that C1q/gC1qR may regulate DC differentiation and function through the DC-SIGN–mediated induction of cell-signaling pathways.
Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques
Authors: Sköld Annette E. , Hasan Maroof , Vargas Leonardo , Saidi Hela , Bosquet Nathalie , Le Grand Roger , Smith C. I. Edvard , Spetz Anna-Lena 
Published: June 2012

Abstract
TLR3 is a key receptor for recognition of double-stranded RNA and initiation of immune responses against viral infections. However, hyperactive responses can have adverse effects, such as virus-induced asthma. Strategies to prevent TLR3-mediated pathology are therefore desired. We investigated the effect of single-stranded DNA oligonucleotides (ssDNA-ODNs) on TLR3 activation. Human monocyte-derived dendritic cells up-regulate maturation markers and secrete proinflammatory cytokines on treatment with the synthetic TLR3 ligand polyinosine-polycytidylic acid (poly I:C). These events were inhibited in cultures with ssDNA-ODNs. Poly I:C activation of nonhematopoietic cells was also inhibited by ssDNA-ODNs. The uptake of poly I:C into cells was reduced in the presence of ssDNA-ODNs, preventing TLR3 engagement from occurring. To confirm this inhibition in vivo, we administered ssDNA-ODNs and poly I:C, alone or in combination, via the intranasal route in cynomolgus macaques. Proinflammatory cytokines were detected in nasal secretions in the poly I:C group, while the levels were reduced in the groups receiving ssDNA-ODNs or both substances. Our results demonstrate that TLR3-triggered immune activation can be modulated by ssDNA-ODNs and provide evidence of dampening proinflammatory cytokine release in the airways of cynomolgus macaques. These findings may open novel perspectives for clinical strategies to prevent or treat inflammatory conditions exacerbated by TLR3 signaling.
Coordinated roles of ST3Gal-VI and ST3Gal-IV sialyltransferases in the synthesis of selectin ligands
Authors: Yang Won Ho , Nussbaum Claudia , Grewal Prabhjit K. , Marth Jamey D. , Sperandio Markus 
Published: June 2012

AbstractBinding of selectins to their glycan ligands is a prerequisite for successful leukocyte trafficking. During synthesis and transport through the secretory pathway, selectin ligands are constructed with the participation of one or more sialyltransferases of the ST3Gal subfamily. Previous studies established that ST3Gal-IV only partially contributes to selectin ligand formation, indicating that other ST3Gal-sialyltransferases are involved. By generating and analyzing St3gal6-null mice and St3gal4/St3gal6 double-deficient mice, in the present study, we found that binding of E- and P-selectin to neutrophils and L-selectin binding to lymph node high endothelial venules is reduced in the absence of ST3Gal-VI and to a greater extent in double-deficient mice. In an ex vivo flow chamber assay, P- and E-selectin–dependent leukocyte rolling was mildly reduced in St3gal6-null mice and more severely in double-deficient mice. In inflamed cremaster muscle venules of St3gal6-null mice, we found impaired P-selectin–dependent, but not E-selectin–dependent leukocyte rolling, whereas in double-deficient mice, E-selectin–dependent rolling was almost completely absent. Furthermore, neutrophil recruitment into the inflamed peritoneal cavity and lymphocyte homing to secondary lymphoid organs were impaired in St3gal6-null mice and more severely in double-deficient mice. The results of the present study demonstrate the coordinated participation of both ST3Gal-VI and ST3Gal-IV in the synthesis of functional selectin ligands.