bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative genomic analysis of the genus Staphylococcus including Staphylococcus aureus and its newly described sister species Staphylococcus simiae
Authors: Suzuki Haruo , Lefébure Tristan , Bitar Paulina Pavinski , Stanhope Michael J 
Published: January 2012

Abstract

Background

Staphylococcus belongs to the Gram-positive low G + C content group of the Firmicutes division of bacteria. Staphylococcus aureus is an important human and veterinary pathogen that causes a broad spectrum of diseases, and has developed important multidrug resistant forms such as methicillin-resistant S. aureus (MRSA). Staphylococcus simiae was isolated from South American squirrel monkeys in 2000, and is a coagulase-negative bacterium, closely related, and possibly the sister group, to S. aureus. Comparative genomic analyses of closely related bacteria with different phenotypes can provide information relevant to understanding adaptation to host environment and mechanisms of pathogenicity.

Results
We determined a Roche/454 draft genome sequence for S. simiae and included it in comparative genomic analyses with 11 other Staphylococcus species including S. aureus. A genome based phylogeny of the genus confirms that S. simiae is the sister group to S. aureus and indicates that the most basal Staphylococcus lineage is Staphylococcus pseudintermedius, followed by Staphylococcus carnosus. Given the primary niche of these two latter taxa, compared to the other species in the genus, this phylogeny suggests that human adaptation evolved after the split of S. carnosus. The two coagulase-positive species (S. aureus and S. pseudintermedius) are not phylogenetically closest but share many virulence factors exclusively, suggesting that these genes were acquired by horizontal transfer. Enrichment in genes related to mobile elements such as prophage in S. aureus relative to S. simiae suggests that pathogenesis in the S. aureus group has developed by gene gain through horizontal transfer, after the split of S. aureus and S. simiae from their common ancestor.

Conclusions
Comparative genomic analyses across 12 Staphylococcus species provide hypotheses about lineages in which human adaptation has taken place and contributions of horizontal transfer in pathogenesis.
Establishment of a leptospirosis model in guinea pigs using an epicutaneous inoculations route
Authors: Zhang Yan , Lou Xiao-Li , Yang Hong-Liang , Guo Xiao-Kui , Zhang Xiang-Yan , He Ping , Jiang Xu-Cheng 
Published: January 2012

Abstract

Background
Leptospires are presumed to enter their host via small abrasions or breaches of the skin. The intraperitoneal route, although commonly used in guinea pig and hamster models of leptospirosis, does not reflect conditions encountered during natural infection. The aim of this study is to develop a novel leptospirosis guinea pig model through epicutaneous route and to elucidate the pathogenesis of leptospirosis in experimental guinea pigs by comparing the data from other studies using different infection routes.

Methods
The guinea pigs were inoculated with 5 × 108
Leptospira interrogans strain Lai onto either shaved-only or abraded skin. The guinea pigs were sacrificed at 2, 8, 24, 48, 72, 96 and 144 h post-infection (p.i.) followed by harvest of the lungs, liver, kidneys, spleen, and the skin around the inoculated sites for further examinations. Hematoxylin and eosin (HE) staining and electron microscopy were used to detect the pathologic changes. Real time PCR and immunohistochemistry staining were performed to detect dynamic distribution of leptospires in blood and tissues, respectively.

Results
In the guinea pigs with abraded skin inoculations, leptospires were detected in blood as early as 2 h post infection (p.i.) and then disseminated to the liver, lungs and kidneys of almost all animals within 96 h p.i.. Leptospires were also detected engulfed in the swelling vascular endothelial cells and were frequently aggregated around the capillaries in the dermis and subcutaneous tissue under the inoculated site. For the guinea pigs with abraded skin inoculations, hemorrhage at the dermis around the inoculated site was found before the appearance of internal organs hemorrhage, severe lesions such as hemorrhages in the lungs, nephritis, jaundice, haematuria were also observed, and two of seven guinea pigs died at 144 h p.i. while no lesions and leptospires were detected in the shaved-only guinea pigs using the same dose of strain Lai.

Conclusion
Intact keratinocyte layer is a very efficient barrier against leptospires, and intact skin can prevent the infiltration of leptosipres to the host. Leptospires can penetrate abraded skin and quickly establish a systemic infection by crossing tissue barriers. We have successfully established a novel leptospirosis guinea pig model through epicutaneous inoculations route, which replicates a natural course of infection and appears to be an alternative way to investigate the pathogenesis of leptospirosis, especially in terms of early stage of host-pathogen interactions. This novel model may also be advantageous for studies of the mechanisms involved in cutaneous barriers and epidermal interactions with this organism.
Physician experience and rates of plasma HIV-1 RNA suppression among illicit drug users: an observational study
Authors: Sangsari Sassan , Milloy M-J , Ibrahim Amir , Kerr Thomas , Zhang Ruth , Montaner Julio , Wood Evan 
Published: January 2012

Abstract

Background
Despite the availability of antiretroviral therapy (ART), suboptimal treatment outcomes have been observed among HIV-seropositive illicit drug users. As there is an urgent need to improve responses to antiretroviral therapy among this population, we undertook this study to evaluate the role of physician experience on rates of plasma HIV-1 RNA suppression following initiation of ART.

Methods
Using data from a community-recruited cohort of HIV-positive illicit drug users, we used Cox proportional hazards regression to model the time to plasma viral HIV RNA < 500 copies/mL among antiretroviral-naïve subjects initiating ART. Physician experience was defined as a continuous variable measured per 100 HIV-infected patients previously enrolled in the province-wide HIV treatment registry by that physician at the time a patient was enrolled.

Results
Between May 1996 and December 2008, 267 individuals initiated ART among whom 227 (85%) achieved a plasma HIV RNA < 500 copies/mL during the study period. In a multivariate analysis, greater physician experience was independently associated with higher rates of plasma HIV RNA suppression (adjusted hazard ratio [AHR] = 1.17, 95% confidence interval [CI]: 1.03-1.34) after adjustment for adherence to ART. Other factors associated with viral suppression included engagement in methadone maintenance therapy (AHR = 1.61, 95% CI: 1.23-2.09), ≥ 95% adherence to ART (AHR = 2.42, 95% CI: 1.80-3.26), baseline CD4 count (AHR = 0.89, 95% CI: 0.83-0.96) and baseline plasma HIV-1 RNA (AHR = 0.65, 95% CI: 0.53-0.81).

Conclusions
In this setting of universal HIV/AIDS care, illicit drug users with more experienced physicians exhibited faster rates of plasma viral load suppression. These findings argue for specialized services to help optimize HIV treatment outcomes among this population.
Biomarkers for antitumor activity of bevacizumab in gastric cancer models
Authors: Yamashita-Kashima Yoriko , Fujimoto-Ouchi Kaori , Yorozu Keigo , Kurasawa Mitsue , Yanagisawa Mieko , Yasuno Hideyuki , Mori Kazushige 
Published: January 2012

Abstract

Background
Bevacizumab is a humanized monoclonal antibody to human vascular endothelial cell growth factor (VEGF) and has been used for many types of cancers such as colorectal cancer, non-small cell lung cancer, breast cancer, and glioblastoma. Bevacizumab might be effective against gastric cancer, because VEGF has been reported to be involved in the development of gastric cancer as well as other cancers. On the other hand, there are no established biomarkers to predict the bevacizumab efficacy in spite of clinical needs. Therefore, we tried to identify the predictive markers for efficacy of bevacizumab in gastric cancer patients by using bevacizumab-sensitive and insensitive tumor models.

Methods
Nine human gastric and two colorectal cancer mouse xenografts were examined for their sensitivity to bevacizumab. We examined expression levels of angiogenic factors by ELISA, bioactivity of VEGF by phosphorylation of VEGFR2 in HUVEC after addition of tumor homogenate, tumor microvessel density by CD31-immunostaining, and polymorphisms of the VEGF gene by HybriProbe™ assay.

Results
Of the 9 human gastric cancer xenograft models used, GXF97, MKN-45, MKN-28, 4-1ST, SC-08-JCK, and SC-09-JCK were bevacizumab-sensitive, whereas SCH, SC-10-JCK, and NCI-N87 were insensitive. The sensitivity of the gastric cancer model to bevacizumab was not related to histological type or HER2 status. All tumors with high levels of VEGF were bevacizumab-sensitive except for one, SC-10-JCK, which had high levels of VEGF. The reason for the refractoriness was non-bioactivity on the phosphorylation of VEGFR2 and micro-vessel formation of VEGF, but was not explained by the VEGF allele or VEGF165b. We also examined the expression levels of other angiogenic factors in the 11 gastrointestinal tumor tissues. In the refractory models including SC-10-JCK, tumor levels of another angiogenic factor, bFGF, were relatively high. The VEGF/bFGF ratio correlated more closely with sensitivity to bevacizumab than with the VEGF level.

Conclusions
VEGF levels and VEGF/bFGF ratios in tumors were related to bevacizumab sensitivity of the xenografts tested. Further clinical investigation into useful predictive markers for bevacizumab sensitivity is warranted.
Shortening of atrioventricular delay at increased atrial paced heart rates improves diastolic filling and functional class in patients with biventricular pacing
Authors: Rafie Reza , Qamruddin Salima , Ozhand Ali , Taha Nima , Naqvi Tasneem Z 
Published: January 2012

Abstract

Background
Use of rate adaptive atrioventricular (AV) delay remains controversial in patients with biventricular (Biv) pacing. We hypothesized that a shortened AV delay would provide optimal diastolic filling by allowing separation of early and late diastolic filling at increased heart rate (HR) in these patients.

Methods
34 patients (75 ± 11 yrs, 24 M, LVEF 34 ± 12%) with Biv and atrial pacing had optimal AV delay determined at baseline HR by Doppler echocardiography. Atrial pacing rate was then increased in 10 bpm increments to a maximum of 90 bpm. At each atrial pacing HR, optimal AV delay was determined by changing AV delay until best E and A wave separation was seen on mitral inflow pulsed wave (PW) Doppler (defined as increased atrial duration from baseline or prior pacemaker setting with minimal atrial truncation). Left ventricular (LV) systolic ejection time and velocity time integral (VTI) at fixed and optimal AV delay was also tested in 13 patients. Rate adaptive AV delay was then programmed according to the optimal AV delay at the highest HR tested and patients were followed for 1 month to assess change in NYHA class and Quality of Life Score as assessed by Minnesota Living with Heart Failure Questionnaire.

Results
81 AV delays were evaluated at different atrial pacing rates. Optimal AV delay decreased as atrial paced HR increased (201 ms at 60 bpm, 187 ms at 70 bpm, 146 ms at 80 bpm and 123 ms at 90 bpm (ANOVA F-statistic = 15, p = 0.0010). Diastolic filling time (P < 0.001 vs. fixed AV delay), mitral inflow VTI (p < 0.05 vs fixed AV delay) and systolic ejection time (p < 0.02 vs. fixed AV delay) improved by 14%, 5% and 4% respectively at optimal versus fixed AV delay at the same HR. NYHA improved from 2.6 ± 0.7 at baseline to 1.7 ± 0.8 (p < 0.01) 1 month post optimization. Physical component of Quality of Life Score improved from 32 ± 17 at baseline to 25 ± 12 (p < 0.05) at follow up.

Conclusions
Increased heart rate by atrial pacing in patients with Biv pacing causes compromise in diastolic filling time which can be improved by AV delay shortening. Aggressive AV delay shortening was required at heart rates in physiologic range to achieve optimal diastolic filling and was associated with an increase in LV ejection time during optimization. Functional class improved at 1 month post optimization using aggressive AV delay shortening algorithm derived from echo-guidance at the time of Biv pacemaker optimization.
Sequence variants of interleukin 6 (IL-6) are significantly associated with a decreased risk of late-onset Alzheimer's disease
Authors: Chen Shih-Yuan , Chen Ta-Fu , Lai Liang-Chuan , Chen Jen-Hau , Sun Yu , Wen Li-Li , Yip Ping-Keung , Chu Yi-Min , Chen Yen-Ching 
Published: January 2012

AbstractBackgroundInterleukin 6 (IL-6) has been related to beta-amyloid aggregation and the appearance of hyperphosphorylated tau in Alzheimer's disease (AD) brain. However, previous studies relatingIL-6genetic polymorphisms to AD included few and unrepresentative single nucleotide polymorphisms (SNPs) and the results were inconsistent.MethodsThis is a case-control study. A total of 266 patients with AD, aged≧65, were recruited from three hospitals in Taiwan (2007-2010). Controls (n = 444) were recruited from routine health checkups and volunteers of the hospital during the same period of time. Three commonIL-6haplotype-tagging SNPs were selected to assess the association betweenIL-6polymorphisms and the risk of late-onset AD (LOAD).ResultsVariant carriers ofIL-6rs1800796 and rs1524107 were significantly associated with a reduced risk of LOAD [(GG + GC vs. CC): adjusted odds ratio (AOR) = 0.64 and (CC + CT vs. TT): AOR = 0.60, respectively]. Haplotype CAT was associated with a decreased risk of LOAD (0 and 1 copy vs. 2 copies: AOR = 0.65, 95% CI = 0.44-0.95). These associations remained significant inApoE e4non-carriers only. Hypertension significantly modified the association between rs2069837 polymorphisms and the risk of LOAD (pinteraction= 0.03).ConclusionsIL-6polymorphisms are associated with reduced risk of LOAD, especially inApoE e4non-carriers. This study identified genetic markers for predicting LOAD inApoE e4non-carriers.
Protein dynamics at Eph receptor-ligand interfaces as revealed by crystallography, NMR and MD simulations
Authors: Qin Haina , Lim Liangzhong , Song Jianxing 
Published: January 2012

Abstract

Background
The role of dynamics in protein functions including signal transduction is just starting to be deciphered. Eph receptors with 16 members divided into A- and B- subclasses are respectively activated by 9 A- and B-ephrin ligands. EphA4 is the only receptor capable of binding to all 9 ephrins and small molecules with overlapped interfaces.

Results
We first determined the structures of the EphA4 ligand binding domain (LBD) in two crystals of P1 space group. Noticeably, 8 EphA4 molecules were found in one asymmetric unit and consequently from two crystals we obtained 16 structures, which show significant conformational variations over the functionally critical A-C, D-E, G-H and J-K loops. The 16 new structures, together with previous 9 ones, can be categorized into two groups: closed and open forms which resemble the uncomplexed and complexed structures of the EphA4 LBD respectively. To assess whether the conformational diversity over the loops primarily results from the intrinsic dynamics, we initiated 30-ns molecular dynamics (MD) simulations for both closed and open forms. The results indicate that the loops do have much higher intrinsic dynamics, which is further unravelled by NMR H/D exchange experiments. During simulations, the open form has the RMS deviations slightly larger than those of the closed one, suggesting the open form may be less stable in the absence of external contacts. Furthermore, no obvious exchange between two forms is observed within 30 ns, implying that they are dynamically separated.

Conclusions
Our study provides the first experimental and computational result revealing that the intrinsic dynamics are most likely underlying the conformational diversity observed for the EphA4 LBD loops mediating the binding affinity and specificity. Interestingly, the open conformation of the EphA4 LBD is slightly unstable in the absence of it natural ligand ephrins, implying that the conformational transition from the closed to open has to be driven by the high-affinity interaction with ephrins because the weak interaction with small molecule was found to be insufficient to trigger the transition. Our results therefore highlight the key role of protein dynamics in Eph-ephrin signalling and would benefit future design of agonists/antagonists targeting Eph receptors.
Association of Family History With Cancer Recurrence and Survival in Patients With Gastric Cancer
Authors: Han Mi Ah , Oh Myueng Guen , Choi Il Ju , Park Sook Ryun , Ryu Keun Won , Nam Byung-Ho , Cho Soo-Jeong , Kim Chan Gyoo , Lee Jun Ho , Kim Young-Woo 
Published: January 2012

Purpose Family history of gastric cancer is a major risk factor for the disease. In this study, we investigated the prognoses of patients with gastric cancer with a family history. Patients and Methods We retrospectively reviewed data from 1,273 patients with gastric adenocarcinoma who had undergone gastrectomy between 2001 and 2005 at a tertiary cancer center hospital. A positive family history was defined as a self-reported history of cancer in first- or second-degree relatives. Patients were followed up until December 2009 for death or recurrence. Clinicopathologic characteristics were compared by family history. Kaplan-Meier plots and Cox proportional hazards regressions were applied for disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS). Results Of 1,273 patients, 263 patients (20.6%) had first-degree relatives with a history of gastric cancer. First-degree family history of gastric cancer was associated with better DFS, RFS, and OS (P = .012, .006, and .005, respectively). In patients with stage I or II gastric cancer, first-degree family history was not associated with survival. However, it was associated with a reduced risk of recurrence or mortality in patients with stage III or IV gastric cancer. Compared with patients without a family history, the adjusted hazard ratios for those with a first-degree family history of gastric cancer were 0.49 (95% CI, 0.29 to 0.84) for DFS, 0.51 (95% CI, 0.30 to 0.87) for RFS, and 0.47 (95% CI, 0.26 to 0.84) for OS in patients with stage III or IV gastric cancer. Conclusion A first-degree family history of gastric cancer is associated with improved survival after curative-intent surgery in patients with stage III or IV gastric cancer.
Hydrodynamics of the bluegill sunfish C-start escape response: three-dimensional simulations and comparison with experimental data
Authors: Borazjani Iman , Sotiropoulos Fotis , Tytell Eric D. , Lauder George V. 
Published: January 2012

SUMMARYIn this work we study the hydrodynamics of a bluegill sunfish performing a C-start maneuver in unprecedented detail using 3-D numerical simulations guided by previous laboratory experiments with live fish. The 3-D fish body geometry and kinematics are reconstructed from the experiments using high-speed video and prescribed as input to the numerical simulation. The calculated instantaneous flow fields at various stages of the C-start maneuver are compared with the two-dimensional particle image velocimetry measurements, and are shown to capture essentially all flow features observed in the measurements with good quantitative accuracy; the simulations reveal the experimentally observed three primary jet flow patterns whose momentum time series are in very good agreement with the measured flow field. The simulations elucidate for the first time the complex 3-D structure of the wake during C-starts, revealing an intricate vortical structure consisting of multiple connected vortex loops at the end of the C-start. We also find that the force calculated based on the 3-D flow field has higher magnitudes than that implied by the jet momentum on the midplane, and it exhibits large and rapid fluctuations during the two stages of the C-start. These fluctuations are physical and are related to the change in the direction of the acceleration of the fish body, which changes the location of the high and low pressure pockets around the fish.
Differences in locomotor performance between individuals: importance of parvalbumin, calcium handling and metabolism
Authors: Seebacher Frank , Walter Isabel 
Published: January 2012

SUMMARY
Locomotor performance is linked to fitness and health of animals and is expected to be under strong selection. However, interindividual variation in locomotor performance is pronounced in many species. It was our aim to investigate the relative importance of energy metabolism and calcium handling in determining sprint and sustained locomotion in the zebrafish (Danio rerio). Sprint and sustained performance (Ucrit) varied independently from each other. Using in vivo electroporation, we found that increased parvalbumin protein concentration improved both sprint and sustained locomotion. This is the first demonstration that parvalbumin plays a role in determining whole-animal performance. High sprint performance fish had greater mRNA concentrations of the metabolic regulators PPARδ and PGC1β compared with fish with poor sprint performance. High sustained performance fish, in contrast, had greater concentrations of PGC-1α and PGC-1β. The increased expression of these metabolic regulators indicates an enhancement of the metabolic machinery in high performance animals. Sprint performance is also enhanced by creatine kinase activity, which may be associated with increased PPARδ mRNA concentration. Ryanodine receptor (RyR) and sarcoplasmic reticulum Ca2+-ATPase 1 (SERCA1) mRNA concentrations were significantly increased in high sustained performance fish, while parvalbumin 2, dihydropyridine (DHPR) receptor and SERCA2 mRNA levels were increased in fish with high sprint velocities. Sustained performance was more sensitive to experimentally induced decreases in RyR and DHPR activity than sprint performance. We provide mechanistic explanations of why locomotor performance differs between individuals, which is important for understanding ecological and sporting success, disease and the evolutionary processes underlying selection.
Preliminary investigation into the use of ultrasound elastography during brain tumour resection
Authors: Chakraborty Aabir , Bamber Jeffrey C , Dorward Neil L 
Published: January 2012

Introduction Differentiation of brain tumours from normal brain, during surgical resection is, in part, based on their differing mechanical properties. Brain tumours have variable stiffness characteristics. Surgical evaluations on stiffness are, at best, subjective. Ultrasound elastography is a non-invasive method for imaging mechanical properties of tissues such as stiffness at depth. It is hypothesized that this technique may assist in differentiating tumour from the brain in an intraoperative setting. Methods This study evaluated the feasibility of the intraoperative use of ultrasound elastography during brain tumour resection. A total of 24 patients were recruited for the study. Surgical findings on tumour stiffness were compared with the elastogram findings. Furthermore, visibility of the brain-tumour interface on ultrasound echography compared with ultrasound elastography was analysed. Results Ultrasound elastography was found to have a sensitivity of 100% and specificity of 75% at detecting that tumour had a different stiffness to the brain when compared with surgical findings. The technique was also found to have a 100% sensitivity and specificity at the detection of intratumoral stiffness heterogeneity compared with surgical findings. The presence of fluid-filled cysts limited the quality of the elastograms. Ultrasound elastography did not detect the brain-tumour interface as accurately as conventional echography. Conclusion These findings suggest that ultrasound elastography in combination with conventional B-mode ultrasound may be a useful adjunct to differentiate tumour from the brain.