Empirical Bayesian Mixture Models for Medical Image Translation

Automatically generating one medical imaging modality from another is known as medical image translation, and has numerous interesting applications. This paper presents an interpretable generative modelling approach to medical image translation. By allowing a common model for group-wise normalisation and segmentation of brain scans to handle missing data, the model allows for predicting entirely missing modalities from one, or a few, MR contrasts. Furthermore, the model can be trained on a fairly small number of subjects. The proposed model is validated on three clinically relevant scenarios. Results appear promising and show that a principled, probabilistic model of the relationship between multi-channel signal intensities can be used to infer missing modalities -- both MR contrasts and CT images.Comment: Accepted to the Simulation and Synthesis in Medical Imaging (SASHIMI) workshop at MICCAI 201

Components of the Hematopoietic Compartments in Tumor Stroma and Tumor-Bearing Mice

Solid tumors are composed of cancerous cells and non-cancerous stroma. A better understanding of the tumor stroma could lead to new therapeutic applications. However, the exact compositions and functions of the tumor stroma are still largely unknown. Here, using a Lewis lung carcinoma implantation mouse model, we examined the hematopoietic compartments in tumor stroma and tumor-bearing mice. Different lineages of differentiated hematopoietic cells existed in tumor stroma with the percentage of myeloid cells increasing and the percentage of lymphoid and erythroid cells decreasing over time. Using bone marrow reconstitution analysis, we showed that the tumor stroma also contained functional hematopoietic stem cells. All hematopoietic cells in the tumor stroma originated from bone marrow. In the bone marrow and peripheral blood of tumor-bearing mice, myeloid populations increased and lymphoid and erythroid populations decreased and numbers of hematopoietic stem cells markedly increased with time. To investigate the function of hematopoietic cells in tumor stroma, we co-implanted various types of hematopoietic cells with cancer cells. We found that total hematopoietic cells in the tumor stroma promoted tumor development. Furthermore, the growth of the primary implanted Lewis lung carcinomas and their metastasis were significantly decreased in mice reconstituted with IGF type I receptor-deficient hematopoietic stem cells, indicating that IGF signaling in the hematopoietic tumor stroma supports tumor outgrowth. These results reveal that hematopoietic cells in the tumor stroma regulate tumor development and that tumor progression significantly alters the host hematopoietic compartment

GRACE risk score: sex-based validity of in-hospital mortality prediction in Canadian patients with acute coronary syndrome

Background: Although there are sex differences in management and outcome of acute coronary syndromes (ACS), sex is not a component of Global Registry of Acute Coronary Events (GRACE) risk score (RS) for in-hospital mortality prediction. We sought to determine the prognostic utility of GRACE RS in men and women, and whether its predictive accuracy would be augmented through sex-based modification of its components. Methods: Canadian men and women enrolled in GRACE and Canadian Registry of Acute Coronary Events were stratified as ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation ACS (NSTE-ACS). GRACE RS was calculated as per original model. Discrimination and calibration were evaluated using the c-statistic and Hosmer-Lemeshow goodness-of-fit test, respectively. Multivariable logistic regression was undertaken to assess potential interactions of sex with GRACE RS components. Results: For the overall cohort (n = 14,422), unadjusted in-hospital mortality rate was higher in women than men (4.5% vs. 3.0%, p < 0.001). Overall, GRACE RS c-statistic and goodness-of-fit test p-value were 0.85 (95%CI 0.83–0.87) and 0.11, respectively. While the RS had excellent discrimination for all subgroups (c-statistics > 0.80), discrimination was lower for women compared to men with STEMI [0.80 (0.75–0.84) vs. 0.86 (0.82–0.89), respectively, p < 0.05]. The goodness-of-fit test showed good calibration for women (p = 0.86), but suboptimal for men (p = 0.031). No significant interaction was evident between sex and RS components (all p > 0.25). Conclusions: The GRACE RS is a valid predictor of in-hospital mortality for both men and women with ACS. The lack of interaction between sex and RS components suggests that sex-based modification is not required

The Moving Junction Protein RON8 Facilitates Firm Attachment and Host Cell Invasion in Toxoplasma gondii

The apicomplexan moving junction (MJ) is a highly conserved structure formed during host cell entry that anchors the invading parasite to the host cell and serves as a molecular sieve of host membrane proteins that protects the parasitophorous vacuole from host lysosomal destruction. While recent work in Toxoplasma and Plasmodium has reinforced the composition of the MJ as an important association of rhoptry neck proteins (RONs) with micronemal AMA1, little is known of the precise role of RONs in the junction or how they are targeted to the neck subcompartment. We report the first functional analysis of a MJ/RON protein by disrupting RON8 in T. gondii. Parasites lacking RON8 are severely impaired in both attachment and invasion, indicating that RON8 enables the parasite to establish a firm clasp on the host cell and commit to invasion. The remaining junction components frequently drag in trails behind invading knockout parasites and illustrate a malformed complex without RON8. Complementation of Δron8 parasites restores invasion and reveals a processing event at the RON8 C-terminus. Replacement of an N-terminal region of RON8 with a mCherry reporter separates regions within RON8 that are necessary for rhoptry targeting and complex formation from those required for function during invasion. Finally, the invasion defects in Δron8 parasites seen in vitro translate to radically impaired virulence in infected mice, promoting a model in which RON8 has a crucial and unprecedented task in committing Toxoplasma to host cell entry

Group 3 ITI Consensus Report: Patient-reported outcome measures associated with implant dentistry

Objectives: The aim of Working Group 3 was to focus on three topics that were assessed using patient-reported outcome measures (PROMs). These topics included the following: (a) the aesthetics of tooth and implant-supported fixed dental prostheses focusing on partially edentulous patients, (b) a comparison of fixed and removable implant-retained prostheses for edentulous populations, and (c) immediate versus early/conventional loading of immediately placed implants in partially edentate patients. PROMs include ratings of satisfaction and oral health-related quality of life (QHRQoL), as well as other indicators, that is, pain, general health-related quality of life (e.g., SF-36). Materials and methods: The Consensus Conference Group 3 participants discussed the findings of the three systematic review manuscripts. Following comprehensive discussions, participants developed consensus statements and recommendations that were then discussed in larger plenary sessions. Following this, any necessary modifications were made and approved. Results: Patients were very satisfied with the aesthetics of implant-supported fixed dental prostheses and the surrounding mucosa. Implant neck design, restorative material, or use of a provisional restoration did not influence patients’ ratings. Edentulous patients highly rate both removable and fixed implant-supported prostheses. However, they rate their ability to maintain their oral hygiene significantly higher with the removable prosthesis. Both immediate provisionalization and conventional loading receive positive patient-reported outcomes. Conclusions: Patient-reported outcome measures should be gathered in every clinical study in which the outcomes of oral rehabilitation with dental implants are investigated. PROMs, such as patients’ satisfaction and QHRQoL, should supplement other clinical parameters in our clinical definition of success

Discovery of nucleotide polymorphisms in the Musa gene pool by Ecotilling

Musa (banana and plantain) is an important genus for the global export market and in local markets where it provides staple food for approximately 400 million people. Hybridization and polyploidization of several (sub)species, combined with vegetative propagation and human selection have produced a complex genetic history. We describe the application of the Ecotilling method for the discovery and characterization of nucleotide polymorphisms in diploid and polyploid accessions of Musa. We discovered over 800 novel alleles in 80 accessions. Sequencing and band evaluation shows Ecotilling to be a robust and accurate platform for the discovery of polymorphisms in homologous and homeologous gene targets. In the process of validating the method, we identified two single nucleotide polymorphisms that may be deleterious for the function of a gene putatively important for phototropism. Evaluation of heterozygous polymorphism and haplotype blocks revealed a high level of nucleotide diversity in Musa accessions. We further applied a strategy for the simultaneous discovery of heterozygous and homozygous polymorphisms in diploid accessions to rapidly evaluate nucleotide diversity in accessions of the same genome type. This strategy can be used to develop hypotheses for inheritance patterns of nucleotide polymorphisms within and between genome types. We conclude that Ecotilling is suitable for diversity studies in Musa, that it can be considered for functional genomics studies and as tool in selecting germplasm for traditional and mutation breeding approaches

Gliding Motility of Babesia bovis Merozoites Visualized by Time-Lapse Video Microscopy

BACKGROUND: Babesia bovis is an apicomplexan intraerythrocytic protozoan parasite that induces babesiosis in cattle after transmission by ticks. During specific stages of the apicomplexan parasite lifecycle, such as the sporozoites of Plasmodium falciparum and tachyzoites of Toxoplasma gondii, host cells are targeted for invasion using a unique, active process termed "gliding motility". However, it is not thoroughly understood how the merozoites of B. bovis target and invade host red blood cells (RBCs), and gliding motility has so far not been observed in the parasite. METHODOLOGY/PRINCIPAL FINDINGS: Gliding motility of B. bovis merozoites was revealed by time-lapse video microscopy. The recorded images revealed that the process included egress of the merozoites from the infected RBC, gliding motility, and subsequent invasion into new RBCs. The gliding motility of B. bovis merozoites was similar to the helical gliding of Toxoplasma tachyzoites. The trails left by the merozoites were detected by indirect immunofluorescence assay using antiserum against B. bovis merozoite surface antigen 1. Inhibition of gliding motility by actin filament polymerization or depolymerization indicated that the gliding motility was driven by actomyosin dependent process. In addition, we revealed the timing of breakdown of the parasitophorous vacuole. Time-lapse image analysis of membrane-stained bovine RBCs showed formation and breakdown of the parasitophorous vacuole within ten minutes of invasion. CONCLUSIONS/SIGNIFICANCE: This is the first report of the gliding motility of B. bovis. Since merozoites of Plasmodium parasites do not glide on a substrate, the gliding motility of B. bovis merozoites is a notable finding

The effects of acute CRAM supplementation on reaction time and subjective measures of focus and alertness in healthy college students

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to examine the effect of acute and prolonged (4-weeks) ingestion of a supplement designed to improve reaction time and subjective measures of alertness, energy, fatigue, and focus compared to placebo.</p> <p>Methods</p> <p>Nineteen physically-active subjects (17 men and 2 women) were randomly assigned to a group that either consumed a supplement (21.1 ± 0.6 years; body mass: 80.6 ± 9.4 kg) or placebo (21.3 ± 0.8 years; body mass: 83.4 ± 18.5 kg). During the initial testing session (T1), subjects were provided 1.5 g of the supplement (CRAM; α-glycerophosphocholine, choline bitartrate, phosphatidylserine, vitamins B3, B6, and B12, folic acid, L-tyrosine, anhydrous caffeine, acetyl-L-carnitine, and naringin) or a placebo (PL), and rested quietly for 10-minutes before completing a questionnaire on subjective feelings of energy, fatigue, alertness and focus (PRE). Subjects then performed a 4-minute quickness and reaction test followed by a 10-min bout of exhaustive exercise. The questionnaire and reaction testing sequence was then repeated (POST). Subjects reported back to the lab (T2) following 4-weeks of supplementation and repeated the testing sequence.</p> <p>Results</p> <p>Reaction time significantly declined (p = 0.050) between PRE and POST at T1 in subjects consuming PL, while subjects under CRAM supplementation were able to maintain (p = 0.114) their performance. Significant performance declines were seen in both groups from PRE to POST at T2. Elevations in fatigue were seen for CRAM at both T1 and T2 (p = 0.001 and p = 0.000, respectively), but only at T2 for PL (p = 0.029). Subjects in CRAM maintained focus between PRE and POST during both T1 and T2 trials (p = 0.152 and p = 0.082, respectively), whereas significant declines in focus were observed between PRE and POST in PL at both trials (p = 0.037 and p = 0.014, respectively). No difference in alertness was seen at T1 between PRE and POST for CRAM (p = 0.083), but a significant decline was recorded at T2 (p = 0.005). Alertness was significantly lower at POST at both T1 and T2 for PL (p = 0.040 and p = 0.33, respectively). No differences in any of these subjective measures were seen between the groups at any time point.</p> <p>Conclusion</p> <p>Results indicate that acute ingestion of CRAM can maintain reaction time, and subjective feelings of focus and alertness to both visual and auditory stimuli in healthy college students following exhaustive exercise. However, some habituation may occur following 4-weeks of supplementation.</p

The Diverse and Dynamic Nature of Leishmania Parasitophorous Vacuoles Studied by Multidimensional Imaging

An important area in the cell biology of intracellular parasitism is the customization of parasitophorous vacuoles (PVs) by prokaryotic or eukaryotic intracellular microorganisms. We were curious to compare PV biogenesis in primary mouse bone marrow-derived macrophages exposed to carefully prepared amastigotes of either Leishmania major or L. amazonensis. While tight-fitting PVs are housing one or two L. major amastigotes, giant PVs are housing many L. amazonensis amastigotes. In this study, using multidimensional imaging of live cells, we compare and characterize the PV biogenesis/remodeling of macrophages i) hosting amastigotes of either L. major or L. amazonensis and ii) loaded with Lysotracker, a lysosomotropic fluorescent probe. Three dynamic features of Leishmania amastigote-hosting PVs are documented: they range from i) entry of Lysotracker transients within tight-fitting, fission-prone L. major amastigote-housing PVs; ii) the decrease in the number of macrophage acidic vesicles during the L. major PV fission or L. amazonensis PV enlargement; to iii) the L. amazonensis PV remodeling after homotypic fusion. The high content information of multidimensional images allowed the updating of our understanding of the Leishmania species-specific differences in PV biogenesis/remodeling and could be useful for the study of other intracellular microorganisms

Data-driven reverse engineering of signaling pathways using ensembles of dynamic models

Signaling pathways play a key role in complex diseases such as cancer, for which the development of novel therapies is a difficult, expensive and laborious task. Computational models that can predict the effect of a new combination of drugs without having to test it experimentally can help in accelerating this process. In particular, network-based dynamic models of these pathways hold promise to both understand and predict the effect of therapeutics. However, their use is currently hampered by limitations in our knowledge of the underlying biochemistry, as well as in the experimental and computational technologies used for calibrating the models. Thus, the results from such models need to be carefully interpreted and used in order to avoid biased predictions. Here we present a procedure that deals with this uncertainty by using experimental data to build an ensemble of dynamic models. The method incorporates steps to reduce overfitting and maximize predictive capability. We find that by combining the outputs of individual models in an ensemble it is possible to obtain a more robust prediction. We report results obtained with this method, which we call SELDOM (enSEmbLe of Dynamic lOgic-based Models), showing that it improves the predictions previously reported for several challenging problems.JRB and DH acknowledge funding from the EU FP7 project NICHE (ITN Grant number 289384). JRB acknowledges funding from the Spanish MINECO project SYNBIOFACTORY (grant number DPI2014-55276-C5-2-R). AFV acknowledges funding from the Galician government (Xunta de Galiza) through the I2C postdoctoral fellowship ED481B2014/133-0. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio