Modeling of hemodynamics arising from malaria infection

We propose a numerical model of hemodynamics arising from malaria infection. This model is based on a particle method, where all the components of blood are represented by the finite number of particles. A two-dimensional spring network of membrane particles is employed for expressing the deformation of malaria infected red blood cells (IRBCs). Malaria parasite within the IRBC is modeled as a rigid object. This model is applied to the stretching of IRBCs by optical tweezers, the deformation of IRBCs in shear flow, and the occlusion of narrow channels by IRBCs. We also investigate the effects of IRBCs on the rheological property of blood in micro-channels. Our results indicate that apparent viscosity is drastically increased for the period from the ring stage and the trophozoite stage, whereas it is not altered in the early stage of infection.     

Two-photon probes for biomedical applications

Two-photon microscopy (TPM), which uses two photons of lower energy as the excitation source, is a vital tool in biology and clinical science, due to its capacity to image deep inside intact tissues for a long period of time. To make TPM a more versatile tool in biomedical research, we have developed a variety of two-photon probes for specific applications. In this mini review, we will briefly discuss two-photon probes for lipid rafts, lysosomes, mitochondria, and pH, and their biomedical applications. [BMB Reports 2013; 46(4): 188-194]     

A systematic review on metabolomics-based diagnostic biomarker discovery and validation in pancreatic cancer

Introduction

Metabolomics is an emerging approach for early detection of cancer. Along with the development of metabolomics, high-throughput technologies and statistical learning, the integration of multiple biomarkers has significantly improved clinical diagnosis and management for patients.

Objectives

In this study, we conducted a systematic review to examine recent advancements in the oncometabolomics-based diagnostic biomarker discovery and validation in pancreatic cancer.

Methods

PubMed, Scopus, and Web of Science were searched for relevant studies published before September 2017. We examined the study designs, the metabolomics approaches, and the reporting methodological quality following PRISMA statement.

Results and Conclusion

The included 25 studies primarily focused on the identification rather than the validation of predictive capacity of potential biomarkers. The sample size ranged from 10 to 8760. External validation of the biomarker panels was observed in nine studies. The diagnostic area under the curve ranged from 0.68 to 1.00 (sensitivity: 0.43–1.00, specificity: 0.73–1.00). The effects of patients’ bio-parameters on metabolome alterations in a context-dependent manner have not been thoroughly elucidated. The most reported candidates were glutamic acid and histidine in seven studies, and glutamine and isoleucine in five studies, leading to the predominant enrichment of amino acid-related pathways. Notably, 46 metabolites were estimated in at least two studies. Specific challenges and potential pitfalls to provide better insights into future research directions were thoroughly discussed. Our investigation suggests that metabolomics is a robust approach that will improve the diagnostic assessment of pancreatic cancer. Further studies are warranted to validate their validity in multi-clinical settings.

     

Effect of spatial inlet velocity profiles on the vortex formation pattern in a dilated left ventricle

Despite the advancement of cardiac imaging technologies, these have traditionally been limited to global geometrical measurements. Computational fluid dynamics (CFD) has emerged as a reliable tool that provides flow ?eld information and other variables essential for the assessment of the cardiac function. Extensive studies have shown that vortex formation and propagation during the filling phase acts as a promising indicator for the diagnosis of the cardiac health condition. Proper setting of the boundary conditions is crucial in a CFD study as they are important determinants, that affect the simulation results. In this article, the effect of different transmitral velocity profiles (parabolic and uniform profile) on the vortex formation patterns during diastole was studied in a ventricle with dilated cardiomyopathy (DCM). The resulting vortex evolution pattern using the uniform inlet velocity profile agreed with that reported in the literature, which revealed an increase in thrombus risk in a ventricle with DCM. However the application of a parabolic velocity profile at the inlet yields a deviated vortical flow pattern and overestimates the propagation velocity of the vortex ring towards the apex of the ventricle. This study highlighted that uniform inlet velocity profile should be applied in the study of the filling dynamics in a left ventricle because it produces results closer to that observed experimentally.     

Trans-regulation of Syndecan Functions by Hetero-oligomerization

Syndecans, a family of transmembrane heparansulfate proteoglycans, are known to interact through their transmembrane domains to form non-covalently linked homodimers, a process essential for their individual functions. Because all syndecan transmembrane domains are highly conserved and thus might mediate interactions between different members of the syndecan family, we investigated syndecan interactions in detail. All recombinant syndecan-2 and -4 protein variants containing the transmembrane domain formed not only sodium dodecyl sulfate (SDS)-resistant homodimers but also SDS-resistant heterodimers. Biochemical and structural data revealed that recombinant syndecan-2 and -4 formed intermolecular interactions in vitro, and the GXXXG motif in transmembrane domain mediated this interaction. When exogenously expressed in rat embryonic fibroblasts, syndecan-2 interacted with syndecan-4 and vice versa. Furthermore, bimolecular fluorescence complementation-based assay demonstrated specific hetero-molecular interactions between syndecan-2 and -4, supporting hetero-oligomer formation of syndecans in vivo. Interestingly, hetero-oligomerization significantly reduced syndecan-4-mediated cellular processes such as protein kinase Cα activation and protein kinase Cα-mediated cell adhesion as well as syndecan-2-mediated tumorigenic activities in colon cancer cells such as migration and anchorage-independent growth. Taken together, these data provide evidence that hetero-oligomerization produces distinct syndecan functions and offer insights into the underlying signaling mechanisms of syndecans.     

Audit of compliance with antenatal protocols.

OBJECTIVE--To assess the implementation of action protocols dictated by antenatal risk factors noted at the initial (booking) antenatal visit. DESIGN--Retrospective study of 2000 women delivered between 1 March 1990 and 29 March 1991. SETTING--Maternity department of a district general hospital supporting a multiethnic population in inner London. MAIN OUTCOME MEASURES--Comparison of clinical actions performed against those dictated by the department''s protocols. Analysis according to clinical importance, gestation at booking, maternal age, parity, birth order, ethnic origin, and certainty of gestational age. RESULTS--Interobserver agreement between the two auditors was good (kappa statistic for risk factors detected, 0.78; for actions generated, 0.80). Of the 15,658 actions dictated by department protocols, 3673 (23.5%) were actually performed by the clinicians. The 63 combinations of risk factors and actions believed by consultants to be of particular clinical importance had an action rate of 28.3% compared with 18.6% for those considered less important (p < 0.001). Mothers who first visited the hospital antenatal clinic at or before 24 weeks'' gestation had 25.2% of relevant protocols fulfilled (p < 0.001). Compliance was significantly improved in women aged 36 or over (32.4%), black women (24.9%), and cases of uncertain gestation (24.5%). Parity and birth order were not associated with an altered action rate. Ethnic origin deemed as "other" (than white, black, Asian, or oriental) or "unknown" was associated with poor compliance (19.3%). CONCLUSIONS--Compliance to a set of agreed protocols was poor even though a computer system was available and a protocol manual had been distributed. Protocols were more likely to be implemented in women who booked early and in some groups of women deemed at high risk including older mothers, black women, and those denoted as having uncertain gestational age.     

In vivo fluorescence imaging of bacteriogenic cyanide in the lungs of live mice infected with cystic fibrosis pathogens

Background

Pseudomonas aeruginosa (PA) and Burkholderia cepacia complex (Bcc), commonly found in the lungs of cystic fibrosis (CF) patients, often produce cyanide (CN), which inhibits cellular respiration. CN in sputa is a potential biomarker for lung infection by CF pathogens. However, its actual concentration in the infected lungs is unknown.

Methods and Findings

This work reports observation of CN in the lungs of mice infected with cyanogenic PA or Bcc strains using a CN fluorescent chemosensor (4′,5′-fluorescein dicarboxaldehyde) with a whole animal imaging system. When the CN chemosensor was injected into the lungs of mice intratracheally infected with either PA or B. cepacia strains embedded in agar beads, CN was detected in the millimolar range (1.8 to 4 mM) in the infected lungs. CN concentration in PA-infected lungs rapidly increased within 24 hours but gradually decreased over the following days, while CN concentration in B. cepacia-infected lungs slowly increased, reaching a maximum at 5 days. CN concentrations correlated with the bacterial loads in the lungs. In vivo efficacy of antimicrobial treatments was tested in live mice by monitoring bacteriogenic CN in the lungs.

Conclusions

The in vivo imaging method was also found suitable for minimally invasive testing the efficacy of antibiotic compounds as well as for aiding the understanding of bacterial cyanogenesis in CF lungs.     

Crystal structure of the GluR0 ligand-binding core from Nostoc punctiforme in complex with L-glutamate: structural dissection of the ligand interaction and subunit interface

GluR0 from Nostoc punctiforme (NpGluR0) is a bacterial homologue of the ionotropic glutamate receptor (iGluR). We have solved the crystal structure of the ligand-binding core of NpGluR0 in complex with l-glutamate at a resolution of 2.1 Å. The structure exhibits a noncanonical ligand interaction and two distinct subunit interfaces. The side-chain guanidium group of Arg80 forms a salt bridge with the γ-carboxyl group of bound l-glutamate: in GluR0 from Synechocystis (SGluR0) and other iGluRs, the equivalent residues are Asn or Thr, which cannot form a similar interaction. We suggest that the local positively charged environment and the steric constraint created by Arg80 mediate the selectivity of l-glutamate binding by preventing the binding of positively charged and hydrophobic amino acids. In addition, the NpGluR0 ligand-binding core forms a new subunit interface in which the two protomers are arranged differently than the known iGluR and SGluR0 dimer interfaces. The significance of there being two different dimer interfaces was investigated using analytical ultracentrifugation analysis.