Project description:PurposeThe aim of this work is to shed light on the issue of reproducibility in MR image reconstruction in the context of a challenge. Participants had to recreate the results of "Advances in sensitivity encoding with arbitrary k-space trajectories" by Pruessmann et al. METHODS: The task of the challenge was to reconstruct radially acquired multicoil k-space data (brain/heart) following the method in the original paper, reproducing its key figures. Results were compared to consolidated reference implementations created after the challenge, accounting for the two most common programming languages used in the submissions (Matlab/Python).ResultsVisually, differences between submissions were small. Pixel-wise differences originated from image orientation, assumed field-of-view, or resolution. The reference implementations were in good agreement, both visually and in terms of image similarity metrics.Discussion and conclusionWhile the description level of the published algorithm enabled participants to reproduce CG-SENSE in general, details of the implementation varied, for example, density compensation or Tikhonov regularization. Implicit assumptions about the data lead to further differences, emphasizing the importance of sufficient metadata accompanying open datasets. Defining reproducibility quantitatively turned out to be nontrivial for this image reconstruction challenge, in the absence of ground-truth results. Typical similarity measures like NMSE of SSIM were misled by image intensity scaling and outlier pixels. Thus, to facilitate reproducibility, researchers are encouraged to publish code and data alongside the original paper. Future methodological papers on MR image reconstruction might benefit from the consolidated reference implementations of CG-SENSE presented here, as a benchmark for methods comparison.
Project description:Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.
Project description:The sense of hearing depends on a specialized sensory organ in the inner ear, called the cochlea, which contains the auditory hair cells (HCs). Noise trauma, infections, genetic factors, side effects of ototoxic drugs (ie, some antibiotics and chemotherapeutics), or simply aging lead to the loss of HCs and their associated primary neurons. This results in irreversible sensorineural hearing loss (SNHL) as in mammals, including humans; the inner ear lacks the capacity to regenerate HCs and spiral ganglion neurons. SNHL is a major global health problem affecting millions of people worldwide and provides a growing concern in the aging population. To date, treatment options are limited to hearing aids and cochlear implants. A major bottleneck for development of new therapies for SNHL is associated to the lack of human otic cell bioassays. Human induced pluripotent stem cells (hiPSCs) can be induced in two-dimensional and three-dimensional otic cells in vitro models that can generate inner ear progenitors and sensory HCs and could be a promising preclinical platform from which to work toward restoring SNHL. We review the potential applications of hiPSCs in the various biological approaches, including disease modeling, bioengineering, drug testing, and autologous stem cell based-cell therapy, that offer opportunities to understand the pathogenic mechanisms of SNHL and identify novel therapeutic strategies.
Project description:Backgroundflorio HAEMO is a new hemophilia treatment monitoring application consisting of a patient smartphone application (app) and a web-based dashboard for healthcare professionals, providing several novel features, including activity tracking, wearable connectivity, kids and caregiver mode, and real-time pharmacokinetic factor level estimation.ObjectivesTo assess intuitiveness, ease-of-use, and patient preference of florio HAEMO in Central Europe using a cross-sectional survey.MethodsThis survey was conducted in six Central European countries between 9 December 2020 and 24 May 2021. The online questionnaire included 17 questions about overall satisfaction, ease-of-use, intuitiveness, and patient preference. Adults or children with hemophilia on regular prophylaxis and using the florio HAEMO app for a minimum of 1 week were invited to complete the online questionnaire by their treating physician.ResultsSixty-six participants took part in the survey. The median duration for all respondents using the florio HAEMO app was 3 to 4 weeks. Overall, 89.4% of users reported being very satisfied or rather satisfied after using florio HAEMO. Of the 23 respondents who had switched from another hemophilia app, 87.0% indicated that they strongly preferred or preferred using florio HAEMO. Most florio HAEMO users reported that the app was very easy or rather easy to use (97.0%) and intuitive (94.0%). florio HAEMO had a positive impact on daily living, with 78.8% of users reporting that the app was very important or rather important to them.ConclusionsThis survey suggests that florio HAEMO is an easy-to-use and intuitive app to assist self-management of home prophylaxis.
Project description:Recombinant influenza virus vaccines based on hemagglutinin (HA) hold the potential to accelerate production timelines and improve efficacy relative to traditional egg-based platforms. Here, we assess a vaccine adjuvant system comprised of immunogenic liposomes that spontaneously convert soluble antigens into a particle format, displayed on the bilayer surface. When trimeric H3 HA was presented on liposomes, antigen delivery to macrophages was improved in vitro, and strong functional antibody responses were induced following intramuscular immunization of mice. Protection was conferred against challenge with a heterologous strain of H3N2 virus, and naive mice were also protected following passive serum transfer. When admixed with the particle-forming liposomes, immunization reduced viral infection severity at vaccine doses as low as 2 ng HA, highlighting dose-sparing potential. In ferrets, immunization induced neutralizing antibodies that reduced the upper respiratory viral load upon challenge with a more modern, heterologous H3N2 viral strain. To demonstrate the flexibility and modular nature of the liposome system, 10 recombinant surface antigens representing distinct influenza virus strains were bound simultaneously to generate a highly multivalent protein particle that with 5 ng individual antigen dosing induced antibodies in mice that specifically recognized the constituent immunogens and conferred protection against heterologous H5N1 influenza virus challenge. Taken together, these results show that stable presentation of recombinant HA on immunogenic liposome surfaces in an arrayed fashion enhances functional immune responses and warrants further attention for the development of broadly protective influenza virus vaccines.
Project description:The recent successes of cryo-electron microscopy fostered great expectation of solving many new and previously recalcitrant biomolecular structures. However, it also brings with it the danger of compromising the validity of the outcomes if not done properly. The Map Challenge is a first step in assessing the state of the art and to shape future developments in data processing. The organizers presented seven cases for single particle reconstruction, and 27 members of the community responded with 66 submissions. Seven groups analyzed these submissions, resulting in several assessment reports, summarized here. We devised a range of analyses to evaluate the submitted maps, including visual impressions, Fourier shell correlation, pairwise similarity and interpretation through modeling. Unfortunately, we did not find strong trends. We ascribe this to the complexity of the challenge, dealing with multiple cases, software packages and processing approaches. This puts the user in the spotlight, where his/her choices becomes the determinant of map quality. The future focus should therefore be on promulgating best practices and encapsulating these in the software. Such practices include adherence to validation principles, most notably the processing of independent sets, proper resolution-limited alignment, appropriate masking and map sharpening. We consider the Map Challenge to be a highly valuable exercise that should be repeated frequently or on an ongoing basis.
Project description:PurposePurpose of this study is to evaluate plan quality on the MRIdian (Viewray Inc., Oakwood Village, OH, USA) system for head and neck cancer (HNC) through comparison of planning approaches of several centers.MethodsA total of 14 planners using the MRIdian planning system participated in this treatment challenge, centrally organized by ViewRay, for one contoured case of oropharyngeal carcinoma with standard constraints for organs at risk (OAR). Homogeneity, conformity, sparing of OARs, and other parameters were evaluated according to The International Commission on Radiation Units and Measurements (ICRU) recommendations anonymously, and then compared between centers. Differences amongst centers were assessed by means of Wilcoxon test. Each plan had to fulfil hard constraints based on dose-volume histogram (DVH) parameters and delivery time. A plan quality metric (PQM) was evaluated. The PQM was defined as the sum of 16 submetrics characterizing different DVH goals.ResultsFor most dose parameters the median score of all centers was higher than the threshold that results in an ideal score. Six participants achieved the maximum number of points for the OAR dose parameters, and none had an unacceptable performance on any of the metrics. Each planner was able to achieve all the requirements except for one which exceeded delivery time. The number of segments correlated to improved PQM and inversely correlated to brainstem D0.1cc and to Planning Target Volume1 (PTV) D0.1cc. Total planning experience inversely correlated to spinal canal dose.ConclusionMagnetic Resonance Image (MRI) linac-based planning for HNC is already feasible with good quality. Generally, an increased number of segments and increasing planning experience are able to provide better results regarding planning quality without significantly prolonging overall treatment time.
Project description:Impaired emotion processing in schizophrenia predicts broader social dysfunction and has been related to negative symptom severity and amygdala dysfunction. Pharmacological modulation of emotion-processing deficits and related neural abnormalities may provide useful phenotypes for pathophysiological investigation.We used an acute benzodiazepine challenge to identify and modulate potential emotion-processing abnormalities in 20 unaffected first-degree relatives of individuals with schizophrenia, compared to 25 control subjects without a family history of psychosis.An oral 1 mg dose of the short-acting anxiolytic benzodiazepine alprazolam was administered in a balanced crossover placebo-controlled double-blind design, preceding identical 3 T fMRI sessions approximately 1 week apart. Primary outcomes included fMRI activity in amygdala and related regions during two facial emotion-processing tasks: emotion identification and emotion memory.Family members exhibited abnormally strong alprazolam-induced reduction in amygdala and hippocampus activation during emotion identification, compared to equal reduction in both groups for the emotion memory task.GABAergic modulation with alprazolam produced differential responses in family members vs. controls, perhaps by unmasking underlying amygdalar and/or GABAergic abnormalities. Such pharmacological fMRI paradigms could prove useful for developing drugs targeting specific neural circuits to treat or prevent schizophrenia.
Project description:We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.