bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccinia virus expressing bone morphogenetic protein-4 in novel glioblastoma orthotopic models facilitates enhanced tumor regression and long-term survival
Authors: Duggal Rohit , Geissinger Ulrike , Zhang Qian , Aguilar Jason , Chen Nanhai G , Binda Elena , Vescovi Angelo L , Szalay Aladar A 
Published: June 2013

Abstract

Background
Glioblastoma multiforme (GBM) is one of the most aggressive forms of cancer with a high rate of recurrence. We propose a novel oncolytic vaccinia virus (VACV)-based therapy using expression of the bone morphogenetic protein (BMP)-4 for treating GBM and preventing recurrence.

Methods
We have utilized clinically relevant, orthotopic xenograft models of GBM based on tumor-biopsy derived, primary cancer stem cell (CSC) lines. One of the cell lines, after being transduced with a cDNA encoding firefly luciferase, could be used for real time tumor imaging. A VACV that expresses BMP-4 was constructed and utilized for infecting several primary glioma cultures besides conventional serum-grown glioma cell lines. This virus was also delivered intracranially upon implantation of the GBM CSCs in mice to determine effects on tumor growth.

Results
We found that the VACV that overexpresses BMP-4 demonstrated heightened replication and cytotoxic activity in GBM CSC cultures with a broad spectrum of activity across several different patient-biopsy cultures. Intracranial inoculation of mice with this virus resulted in a tumor size equal to or below that at the time of injection. This resulted in survival of 100% of the treated mice up to 84 days post inoculation, significantly superior to that of a VACV lacking BMP-4 expression. When mice with a higher tumor burden were injected with the VACV lacking BMP-4, 80% of the mice showed tumor recurrence. In contrast, no recurrence was seen when mice were injected with the VACV expressing BMP-4, possibly due to induction of differentiation in the CSC population and subsequently serving as a better host for VACV infection and oncolysis. This lack of recurrence resulted in superior survival in the BMP-4 VACV treated group.

Conclusions
Based on these findings we propose a novel VACV therapy for treating GBM, which would allow tumor specific production of drugs in the future in combination with BMPs which would simultaneously control tumor maintenance and facilitate CSC differentiation, respectively, thereby causing sustained tumor regression without recurrence.
INI1/hSNF5-interaction defective HIV-1 IN mutants exhibit impaired particle morphology, reverse transcription and integration in vivo
Authors: Mathew Sheeba , Nguyen Minh , Wu Xuhong , Pal Achintya , Shah Vaibhav B , Prasad Vinayaka R , Aiken Christopher , Kalpana Ganjam V 
Published: June 2013

Abstract

Background
Retroviral integrase catalyzes integration of viral DNA into the host genome. Integrase interactor (INI)1/hSNF5 is a host factor that binds to HIV-1 IN within the context of Gag-Pol and is specifically incorporated into HIV-1 virions during assembly. Previous studies have indicated that INI1/hSNF5 is required for late events in vivo and for integration in vitro. To determine the effects of disrupting the IN-INI1 interaction on the assembly and infectivity of HIV-1 particles, we isolated mutants of IN that are defective for binding to INI1/hSNF5 and tested their effects on HIV-1 replication.

Results
A reverse yeast two-hybrid system was used to identify INI1-interaction defective IN mutants (IID-IN). Since protein-protein interactions depend on the surface residues, the IID-IN mutants that showed high surface accessibility on IN crystal structures (K71R, K111E, Q137R, D202G, and S147G) were selected for further study. In vitro interaction studies demonstrated that IID-IN mutants exhibit variable degrees of interaction with INI1. The mutations were engineered into HIV-1NL4-3 and HIV-Luc viruses and tested for their effects on virus replication. HIV-1 harboring IID-IN mutations were defective for replication in both multi- and single-round infection assays. The infectivity defects were correlated to the degree of INI1 interaction of the IID-IN mutants. Highly defective IID-IN mutants were blocked at early and late reverse transcription, whereas partially defective IID-IN mutants proceeded through reverse transcription and nuclear localization, but were partially impaired for integration. Electron microscopic analysis of mutant particles indicated that highly interaction-defective IID-IN mutants produced morphologically aberrant virions, whereas the partially defective mutants produced normal virions. All of the IID-IN mutant particles exhibited normal capsid stability and reverse transcriptase activity in vitro.

Conclusions
Our results demonstrate that a severe defect in IN-INI1 interaction is associated with production of defective particles and a subsequent defect in post-entry events. A partial defect in IN-INI1 interaction leads to production of normal virions that are partially impaired for early events including integration. Our studies suggest that proper interaction of INI1 with IN within Gag-Pol is necessary for proper HIV-1 morphogenesis and integration.
Cognitive function and number of teeth in a community-dwelling population in Japan
Authors: Saito Yuki , Sugawara Norio , Yasui-Furukori Norio , Takahashi Ippei , Nakaji Shigeyuki , Kimura Hiroto 
Published: June 2013

Abstract

Background
It has been reported that oral health is poor in elderly populations and is associated with poor cognition and dementia. The objective of this study was to examine the association between tooth loss and cognitive function in a community-dwelling population in Japan.

Methods
We examined the association between tooth loss and cognitive function in 462 Japanese community-dwelling individuals. The Mini-Mental State Examination (MMSE) was employed to measure global cognitive status. A multiple logistic regression analysis, with both crude and adjusted conditions for confounding factors, was used to assess the relationship between poor cognition and the number of remaining teeth.

Results
The overall prevalence of poor cognition (MMSE ≤ 23) in this study population was 5.6%. Subjects with poor cognition were significantly older, less educated, scored lower in intellectual activity, and had fewer remaining teeth than those with normal cognition. According to the multiple logistic regression analysis, a lower number of teeth (0–10) was found to be a significant independent risk factor (OR = 20.21, 95% confidence interval = 2.20 to 185.47) of cognitive impairment.

Conclusions
This cross-sectional study on a Japanese community-dwelling population revealed relationships between tooth loss and cognitive function. However, the interpretation of our results was hampered by a lack of data, including socioeconomic status and longitudinal observations. Future research exploring tooth loss and cognitive function is warranted.
Medicinal plants from swidden fallows and sacred forest of the Karen and the Lawa in Thailand
Authors: Junsongduang Auemporn , Balslev Henrik , Inta Angkhana , Jampeetong Arunothai , Wangpakapattanawong Prasit 
Published: June 2013

Abstract

Background
Many ecosystem services provided by forests are important for the livelihoods of indigenous people. Sacred forests are used for traditional practices by the ethnic minorities in northern Thailand and they protect these forests that are important for their culture and daily life. Swidden fallow fields are a dominant feature of the agricultural farming landscapes in the region. In this study we evaluate and compare the importance of swidden fallow fields and sacred forests as providers of medicinal plants among the Karen and Lawa ethnic minorities in northern Thailand.

Methods
We made plant inventories in swidden fallow fields of three different ages (1–2, 3–4, 5–6 years old) and in sacred forests around two villages using a replicated stratified design of vegetation plots. Subsequently we interviewed the villagers, using semi-structured questionnaires, to assess the medicinal use of the species encountered in the vegetation survey.

Results
We registered a total of 365 species in 244 genera and 82 families. Of these 72(19%) species in 60(24%) genera and 32(39%) families had medicinal uses. Although the sacred forest overall housed more species than the swidden fallow fields, about equal numbers of medicinal plants were derived from the forest and the fallows. This in turn means that a higher proportion (48% and 34%) of the species in the relatively species poor fallows were used for medicinal purposes than the proportion of medicinal plants from the sacred forest which accounted for 17–22%. Of the 32 medicinal plant families Euphorbiaceae and Lauraceae had most used species in the Karen and Lawa villages respectively.

Conclusion
Sacred forest are important for providing medicinal plant species to the Karen and Lawa communities in northern Thailand, but the swidden fallows around the villages are equally important in terms of absolute numbers of medicinal plant species, and more important if counted as proportion of the total number of species in a habitat. This points to the importance of secondary vegetation as provider of medicinal plants around rural villages as seen elsewhere in the tropics.
Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance
Authors: Xu Lijuan , Wang Hao , Yang Xianle , Lu Liqun 
Published: June 2013

Abstract

Background
Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain.

Results
The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5 - 3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation.

Conclusions
Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics.
Temporary organ displacement coupled with image-guided, intensity-modulated radiotherapy for paraspinal tumors
Authors: Katsoulakis Evangelia , Solomon Stephen B , Maybody Majid , Housman Douglas , Niyazov Greg , Riaz Nadeem , Lovelock Michael , Spratt Daniel E , Erinjeri Joseph P , Thornton Raymond H , Yamada Yoshiya 
Published: June 2013

Abstract

Background
To investigate the feasibility and dosimetric improvements of a novel technique to temporarily displace critical structures in the pelvis and abdomen from tumor during high-dose radiotherapy.

Methods
Between 2010 and 2012, 11 patients received high-dose image-guided intensity-modulated radiotherapy with temporary organ displacement (TOD) at our institution. In all cases, imaging revealed tumor abutting critical structures. An all-purpose drainage catheter was introduced between the gross tumor volume (GTV) and critical organs at risk (OAR) and infused with normal saline (NS) containing 5-10% iohexol. Radiation planning was performed with the displaced OARs and positional reproducibility was confirmed with cone-beam CT (CBCT). Patients were treated within 36 hours of catheter placement. Radiation plans were re-optimized using pre-TOD OARs to the same prescription and dosimetrically compared with post-TOD plans. A two-tailed permutation test was performed on each dosimetric measure.

Results
The bowel/rectum was displaced in six patients and kidney in four patients. One patient was excluded due to poor visualization of the OAR; thus 10 patients were analyzed. A mean of 229 ml (range, 80–1000) of NS 5-10% iohexol infusion resulted in OAR mean displacement of 17.5 mm (range, 7–32). The median dose prescribed was 2400 cGy in one fraction (range, 2100–3000 in 3 fractions). The mean GTV Dmin and PTV Dmin pre- and post-bowel TOD IG-IMRT dosimetry significantly increased from 1473 cGy to 2086 cGy (p=0.015) and 714 cGy to 1214 cGy (p=0.021), respectively. TOD increased mean PTV D95 by 27.14% of prescription (p=0.014) while the PTV D05 decreased by 9.2% (p=0.011). TOD of the bowel resulted in a 39% decrease in mean bowel Dmax (p=0.008) confirmed by CBCT. TOD of the kidney significantly decreased mean kidney dose and Dmax by 25% (0.022).

Conclusions
TOD was well tolerated, reproducible, and facilitated dose escalation to previously radioresistant tumors abutting critical structures while minimizing dose to OARs.
A semi-supervised boosting SVM for predicting hot spots at protein-protein Interfaces
Authors: Xu Bin , Wei Xiaoming , Deng Lei , Guan Jihong , Zhou Shuigeng 
Published: June 2013

Abstract

Background
Hot spots are residues contributing the most of binding free energy yet accounting for a small portion of a protein interface. Experimental approaches to identify hot spots such as alanine scanning mutagenesis are expensive and time-consuming, while computational methods are emerging as effective alternatives to experimental approaches.

Results
In this study, we propose a semi-supervised boosting SVM, which is called sbSVM, to computationally predict hot spots at protein-protein interfaces by combining protein sequence and structure features. Here, feature selection is performed using random forests to avoid over-fitting. Due to the deficiency of positive samples, our approach samples useful unlabeled data iteratively to boost the performance of hot spots prediction. The performance evaluation of our method is carried out on a dataset generated from the ASEdb database for cross-validation and a dataset from the BID database for independent test. Furthermore, a balanced dataset with similar amounts of hot spots and non-hot spots (65 and 66 respectively) derived from the first training dataset is used to further validate our method. All results show that our method yields good sensitivity, accuracy and F1 score comparing with the existing methods.

Conclusion
Our method boosts prediction performance of hot spots by using unlabeled data to overcome the deficiency of available training data. Experimental results show that our approach is more effective than the traditional supervised algorithms and major existing hot spot prediction methods.
Cliques for the identification of gene signatures for colorectal cancer across population
Authors: Pradhan Meeta P , Nagulapalli Kshithija , Palakal Mathew J 
Published: June 2013

Abstract

Background
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. Studies have correlated risk of CRC development with dietary habits and environmental conditions. Gene signatures for any disease can identify the key biological processes, which is especially useful in studying cancer development. Such processes can be used to evaluate potential drug targets. Though recognition of CRC gene-signatures across populations is crucial to better understanding potential novel treatment options for CRC, it remains a challenging task.

Results
We developed a topological and biological feature-based network approach for identifying the gene signatures across populations. In this work, we propose a novel approach of using cliques to understand the variability within population. Cliques are more conserved and co-expressed, therefore allowing identification and comparison of cliques across a population which can help researchers study gene variations. Our study was based on four publicly available expression datasets belonging to four different populations across the world. We identified cliques of various sizes (0 to 7) across the four population networks. Cliques of size seven were further analyzed across populations for their commonality and uniqueness. Forty-nine common cliques of size seven were identified. These cliques were further analyzed based on their connectivity profiles. We found associations between the cliques and their connectivity profiles across networks. With these clique connectivity profiles (CCPs), we were able to identify the divergence among the populations, important biological processes (cell cycle, signal transduction, and cell differentiation), and related gene pathways. Therefore the genes identified in these cliques and their connectivity profiles can be defined as the gene-signatures across populations. In this work we demonstrate the power and effectiveness of cliques to study CRC across populations.

Conclusions
We developed a new approach where cliques and their connectivity profiles helped elucidate the variation and similarity in CRC gene profiles across four populations with unique dietary habits.
Detection of protein complexes from affinity purification/mass spectrometry data
Authors: Cai Bingjing , Wang Haiying , Zheng Huiru , Wang Hui 
Published: June 2013

Abstract

Background
Recent advances in molecular biology have led to the accumulation of large amounts of data on protein-protein interaction networks in different species. An important challenge for the analysis of these data is to extract functional modules such as protein complexes and biological processes from networks which are characterised by the present of a significant number of false positives. Various computational techniques have been applied in recent years. However, most of them treat protein interaction as binary. Co-complex relations derived from affinity purification/mass spectrometry (AP-MS) experiments have been largely ignored.

Methods
This paper presents a new algorithm for detecting protein complexes from AP-MS data. The algorithm intends to detect groups of prey proteins that are significantly co-associated with the same set of bait proteins. We first construct AP-MS data as a bipartite network, where one set of nodes consists of bait proteins and the other set is composed of prey proteins. We then calculate pair-wise similarities of bait proteins based on the number of their commonly shared neighbours. A hierarchical clustering algorithm is employed to cluster bait proteins based on the similarities and thus a set of 'seed' clusters is obtained. Starting from these 'seed' clusters, an expansion process is developed to identify prey proteins which are significantly associated with the same set of bait proteins. Then, a set of complete protein complexes is derived. In application to two real AP-MS datasets, we validate biological significance of predicted protein complexes by using curated protein complexes and well-characterized cellular component annotation from Gene Ontology (GO). Several statistical metrics have been applied for evaluation.

Results
Experimental results show that, the proposed algorithm achieves significant improvement in detecting protein complexes from AP-MS data. In comparison to the well-known MCL algorithm, our algorithm improves the accuracy rate by about 20% in detecting protein complexes in both networks and increases the F-Measure value by about 50% in Krogan_2006 network. Greater precision and better accuracy have been achieved and the identified complexes are demonstrated to match well with existing curated protein complexes.

Conclusions
Our study highlights the significance of taking co-complex relations into account when extracting protein complexes from AP-MS data. The algorithm proposed in this paper can be easily extended to the analysis of other biological networks which can be conveniently represented by bipartite graphs such as drug-target networks.
Module-based subnetwork alignments reveal novel transcriptional regulators in malaria parasite Plasmodium falciparum
Authors: Cai Hong , Hong Changjin , Gu Jianying , Lilburn Timothy G , Kuang Rui , Wang Yufeng 
Published: June 2013

AbstractBackgroundMalaria causes over one million deaths annually, posing an enormous health and economic burden in endemic regions. The completion of genome sequencing of the causative agents, a group of parasites in the genusPlasmodium, revealed potential drug and vaccine candidates. However, genomics-driven target discovery has been significantly hampered by our limited knowledge of the cellular networks associated with parasite development and pathogenesis. In this paper, we propose an approach based on aligning neighborhood PPI subnetworks across species to identify network components in the malaria parasiteP. falciparum.ResultsInstead of only relying on sequence similarities to detect functional orthologs, our approach measures the conservation between the neighborhood subnetworks in protein-protein interaction (PPI) networks in two species,P. falciparumandE. coli. 1,082P. falciparumproteins were predicted as functional orthologs of known transcriptional regulators in theE. colinetwork, including general transcriptional regulators, parasite-specific transcriptional regulators in the ApiAP2 protein family, and other potential regulatory proteins. They are implicated in a variety of cellular processes involving chromatin remodeling, genome integrity, secretion, invasion, protein processing, and metabolism.ConclusionsIn this proof-of-concept study, we demonstrate that a subnetwork alignment approach can reveal previously uncharacterized members of the subnetworks, which opens new opportunities to identify potential therapeutic targets and provide new insights into parasite biology, pathogenesis and virulence. This approach can be extended to other systems, especially those with poor genome annotation and a paucity of knowledge about cellular networks.