The curious case of (caffeine).(benzoic acid): how heteronuclear seeding allowed the formation of an elusive cocrystal

Cocrystals are modular multicomponent solids with exceptional utility in synthetic chemistry and materials science. A variety of methods exist for the preparation of cocrystals yet, some promising cocrystal phases have proven to be intractable synthetic targets. We describe a strategy for the synthesis of the pharmaceutically relevant (caffeine).(benzoic acid) cocrystal (1), which persistently failed to form using a broad range of established techniques. State-of-the-art crystal structure prediction methods were employed to assess the possible existence of a thermodynamically stable form of 1, and to identify appropriate heteronuclear seeds for corystallization. Once introduced, the designed heteronuclear seeds facilitated the formation of 1 and, significantly, continued to act as long-lasting laboratory .contaminants., which encouraged cocrystal formation even when present at such low levels as to evade detection. The seeding technique described thus enables the synthesis of cocrystals regarded as unobtainable under desired conditions, and potentially signifies a new direction in the field of materials research

Moving Away from Solely MCQ-based Exams: Short Answer Questions for Enhancing the Variety of Assessment Methods in the Large Classroom

PATH30030 Haematology/Immunosuppression is a UCD level 3 (NFQ level 8) Pathology module in Medicine worth 5.0 ECTS credits. The module is designed for the combined cohort of Stage 2 Graduate Entry Medicine (GEM) and Stage 4 Undergraduate Medicine (UgM) Programmes (including a group of Malaysian students) for the maximum number of 315 students, from all over the world. The students have diverse educational, cultural and ethnic backgrounds. 190 This module outlines the diseases of the peripheral blood, bone marrow and lymph nodes and their treatment. It includes the principles of transfusion, the study of infective agents seen in the immunocompromised patient, helminths and infections seen in the returned traveller and their treatment. Pathology, Medical Microbiology and Pharmacology contents are delivered in this module by academic staff and clinicians. Previously, the assessment on this module was purely multiple-choice question (MCQ) based end-of-semester examination (N=90; 100% of module grade) (Table 1). In Medicine, MCQ based examinations are favoured because they enable assessment of large amounts of content/knowledge, and it is possible to grade them by computer (and generate associated statistics) (Epstein, 2007; Table 2). The latter is especially beneficial if large numbers of students are enrolled to the programme. However, MCQs cannot assess problem-solving ability and clinical reasoning skills which medical students need to develop. In addition, students might guess the correct answer reinforcing false knowledge. Student feedback revealed that students do not like the pure MCQ based examinations, and suggested including some element of continuous assessment, and a written part to the exit exam. The student feedback also indicated that they would learn more if there was a written part to the exam

Predicted 'wiring landscape' of Ras-effector interactions in 29 human tissues

Ras is a plasma membrane (PM)-associated signaling hub protein that interacts with its partners (effectors) in a mutually exclusive fashion. We have shown earlier that competition for binding and hence the occurrence of specific binding events at a hub protein can modulate the activation of downstream pathways. Here, using a mechanistic modeling approach that incorporates high-quality proteomic data of Ras and 56 effectors in 29 (healthy) human tissues, we quantified the amount of individual Ras-effector complexes, and characterized the (stationary) Ras "wiring landscape" specific to each tissue. We identified nine effectors that are in significant amount in complex with Ras in at least one of the 29 tissues. We simulated both mutant- and stimulus-induced network re-configurations, and assessed their divergence from the reference scenario, specifically discussing a case study for two stimuli in three epithelial tissues. These analyses pointed to 32 effectors that are in significant amount in complex with Ras only if they are additionally recruited to the PM, e.g. via membrane-binding domains or domains binding to activated receptors at the PM. Altogether, our data emphasize the importance of tissue context for binding events at the Ras signaling hub

Integrating network reconstruction with mechanistic modeling to predict cancer therapies

Signal transduction networks (STNs) are often rewired in cancerous cells. Effective cancer treatment requires identifying and repairing these harmful alterations. We developed a computational framework which can identify these aberrations and predict potential targets for intervention. It reconstructs network models of STNs from noisy and incomplete perturbation response data, and then uses the reconstructed networks to develop mechanistic models of STNs for predicting potential treatments. As a proof of principle, we analysed a perturbation dataset targeting Epidermal Growth Factor Receptor (EGFR) and Insulin like 2 Growth Factor 1 Receptor (IGF1R) pathways in a panel of colorectal cancer (CRC) cells, revealing cell line specific STN rewiring. Specifically, we found that the feedback inhibition of IRS1 by p70S6K is associated with resistance to EGF receptor (EGFR) inhibition, and disrupting this feedback may restore sensitivity to EGFR inhibitors in CRC cells. These findings were experimentally validated in vitro and in zebrafish (Danio rerio) xenografts.European Commission - Seventh Framework Programme (FP7)Science Foundation Irelan

Integrating network reconstruction with mechanistic modeling to predict cancer therapies

Signal transduction networks (STNs) are often rewired in cancerous cells. Effective cancer treatment requires identifying and repairing these harmful alterations. We developed a computational framework which can identify these aberrations and predict potential targets for intervention. It reconstructs network models of STNs from noisy and incomplete perturbation response data, and then uses the reconstructed networks to develop mechanistic models of STNs for predicting potential treatments. As a proof of principle, we analysed a perturbation dataset targeting Epidermal Growth Factor Receptor (EGFR) and Insulin like 2 Growth Factor 1 Receptor (IGF1R) pathways in a panel of colorectal cancer (CRC) cells, revealing cell line specific STN rewiring. Specifically, we found that the feedback inhibition of IRS1 by p70S6K is associated with resistance to EGF receptor (EGFR) inhibition, and disrupting this feedback may restore sensitivity to EGFR inhibitors in CRC cells. These findings were experimentally validated in vitro and in zebrafish (Danio rerio) xenografts.European Commission - Seventh Framework Programme (FP7)Science Foundation Irelan

Disease–Gene Networks of Skin Pigmentation Disorders and Reconstruction of Protein–Protein Interaction Networks

Melanin, a light and free radical absorbing pigment, is produced in melanocyte cells that are found in skin, but also in hair follicles, eyes, the inner ear, heart, brain and other organs. Melanin synthesis is the result of a complex network of signaling and metabolic reactions. It therefore comes as no surprise that mutations in many of the genes involved are associated with various types of pigmentation diseases and phenotypes (‘pigmentation genes’). Here, we used bioinformatics tools to first reconstruct gene-disease/phenotype associations for all pigmentation genes. Next, we reconstructed protein–protein interaction (PPI) networks centered around pigmentation gene products (‘pigmentation proteins’) and supplemented the PPI networks with protein expression information obtained by mass spectrometry in a panel of melanoma cell lines (both pigment producing and non-pigment producing cells). The analysis provides a systems network representation of all genes/ proteins centered around pigmentation and melanin biosynthesis pathways (‘pigmentation network map’). Our work will enable the pigmentation research community to experimentally test new hypothesis arising from the pigmentation network map and to identify new targets for drug discovery