Inhibition of protein-peptide interactions by small molecules

In all kinds of disease models, many proteins involved in protein-protein interactions (PPIs) are mutated and do not function properly. The important role of PPIs in disease makes the design of small molecule inhibition an interesting proposition. This project looks at mouse double minute 2 (MDM2) and mouse double minute X (MDMX) which binds and inhibits the tumour suppressor protein p53. MDM2 and MDMX are therefore attractive therapeutic targets due to their role in tumour progression. The aim is to identify small molecule dual inhibitors that are able to disrupt MDM2 and MDMX from binding to p53. Both N-terminal MDM2 and MDMX were successfully expressed and purified with high purity and decent yield. These proteins were used to develop Fluoresence Polarization (FP) and Capillary Electrophoresis (CE) assays for small molecule inhibitors screening. This work has successfully developed FP and CE assays for detecting weakly interacting fragments. The CE assay is a novel method for detecting weak fragments for protein-protein interactions, which are a challenging target. Two approaches were employed to identify small molecule inhibitors for MDM2- N/p53 interaction. At first, small molecules were identified using in silico screening and these hits were verified using FP and CE assays. Second, analogue exploration was applied to identify fragments from the small molecule inhibitors discovered from the in silico screening. Diphenylamine and oxindole fragments were identified as the most potent. However, diphenylamine fragment was discovered to aggregate MDM2-N and was ranked as a false positive hit. No protein aggregation was found when incubated with the oxindole fragment. Therefore oxindole can provide a good starting point for the design of higher affinity analogues. Studying the interaction of MDMX has only recently been undertaken. MDMX contains a high homology binding site with MDM2. Hence, developing a dual MDM2/MDMX inhibitor has become an attractive target to focus on. FP and CE assays were developed to screen compounds against MDMX-N. In silico screening against MDM2-N and MDMX-N found several hits. One compound was discovered as a dual binder to MDM2-N and MDMX-N with low μM affinity. This novel hit is potentially a good starting point for the design of higher affinity analogues

Prevalent Hallucinations during Medical Internships: Phantom Vibration and Ringing Syndromes

Background: Phantom vibration syndrome is a type of hallucination reported among mobile phone users in the general population. Another similar perception, phantom ringing syndrome, has not been previously described in the medical literature. Methods: A prospective longitudinal study of 74 medical interns (46 males, 28 females; mean age, 24.8±1.2 years) was conducted using repeated investigations of the prevalence and associated factors of phantom vibration and ringing. The accompanying symptoms of anxiety and depression were evaluated with the Beck Anxiety and Depression Inventories before the internship began, and again at the third, sixth, and twelfth internship months, and two weeks after the internship ended. Results: The baseline prevalence of phantom vibration was 78.1%, which increased to 95.9% and 93.2% in the third and sixth internship months. The prevalence returned to 80.8% at the twelfth month and decreased to 50.0% 2 weeks after the internship ended. The baseline prevalence of phantom ringing was 27.4%, which increased to 84.9%, 87.7%, and 86.3% in the third, sixth, and twelfth internship months, respectively. This returned to 54.2% two weeks after the internship ended. The anxiety and depression scores also increased during the internship, and returned to baseline two weeks after the internship. There was no significant correlation between phantom vibration/ringing and symptoms of anxiety or depression. The incidence of both phantom vibration and ringing syndromes significantly increased during the internship, and subsequent recovery. Conclusion: This study suggests that phantom vibration and ringing might be entities that are independent of anxiety or depression during evaluation of stress-associated experiences during medical internships

MARS: Message Passing for Antenna and RF Chain Selection for Hybrid Beamforming in MIMO Communication Systems

In this paper, we consider a prospective receiving hybrid beamforming structure consisting of several radio frequency (RF) chains and abundant antenna elements in multi-input multi-output (MIMO) systems. Due to conventional costly full connections, we design an enhanced partially-connected beamformer employing low-density parity-check (LDPC) based structure. As a benefit of LDPC-based structure, information can be exchanged among clustered RF/antenna groups, which results in a low computational complexity order. Advanced message passing (MP) capable of inferring and transferring data among different paths is designed to support LDPC-based hybrid beamformer. We propose a message passing enhanced antenna and RF chain selection (MARS) scheme to minimize the operational power of antennas and RF chains of the receiver. Furthermore, sequential and parallel MP for MARS are respectively designed as MARS-S and MARS-P schemes to address convergence speed issue. Simulations have validated the convergence of both the MARS-P and the MARS-S algorithms. Owing to asynchronous information transfer of MARS-P, it reveals that higher power is required than that of MARS-S, which strikes a compelling balance between power consumption, convergence, and computational complexity. It is also demonstrated that the proposed MARS scheme outperforms the existing benchmarks using heuristic method of fully-/partially-connected architectures in open literature in terms of the lowest power and highest energy efficiency

DreaMo: Articulated 3D Reconstruction From A Single Casual Video

Articulated 3D reconstruction has valuable applications in various domains, yet it remains costly and demands intensive work from domain experts. Recent advancements in template-free learning methods show promising results with monocular videos. Nevertheless, these approaches necessitate a comprehensive coverage of all viewpoints of the subject in the input video, thus limiting their applicability to casually captured videos from online sources. In this work, we study articulated 3D shape reconstruction from a single and casually captured internet video, where the subject's view coverage is incomplete. We propose DreaMo that jointly performs shape reconstruction while solving the challenging low-coverage regions with view-conditioned diffusion prior and several tailored regularizations. In addition, we introduce a skeleton generation strategy to create human-interpretable skeletons from the learned neural bones and skinning weights. We conduct our study on a self-collected internet video collection characterized by incomplete view coverage. DreaMo shows promising quality in novel-view rendering, detailed articulated shape reconstruction, and skeleton generation. Extensive qualitative and quantitative studies validate the efficacy of each proposed component, and show existing methods are unable to solve correct geometry due to the incomplete view coverage.Comment: Project page: https://ttaoretw.github.io/DreaMo

High ERCC1 expression predicts cisplatin-based chemotherapy resistance and poor outcome in unresectable squamous cell carcinoma of head and neck in a betel-chewing area

<p>Abstract</p> <p>Background</p> <p>This study was to evaluate the effect of excision repair cross-complementation group 1(ERCC1) expression on response to cisplatin-based induction chemotherapy (IC) followed by concurrent chemoradiation (CCRT) in locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) patients.</p> <p>Methods</p> <p>Fifty-seven patients with locally advanced unresectable HNSCC who received cisplatin-based IC followed by CCRT from January 1, 2006 through January 1, 2008. Eligibility criteria included presence of biopsy-proven HNSCC without a prior history of chemotherapy or radiotherapy. Immunohistochemistry was used to assess ERCC1 expression in pretreatment biopsy specimens from paraffin blocks. Clinical parameters, including smoking, alcohol consumption and betel nuts chewing, were obtained from the medical records.</p> <p>Results</p> <p>The 12-month progression-free survival (PFS) and 2-year overall survival (OS) rates of fifty-seven patients were 61.1% and 61.0%, respectively. Among these patients, thirty-one patients had low ERCC1 expression and forty-one patients responded to IC followed by CCRT. Univariate analyses showed that patients with low expression of ERCC1 had a significantly higher 12-month PFS rates (73.3% vs. 42.3%, p < 0.001) and 2-year OS (74.2 vs. 44.4%, p = 0.023) rates. Multivariate analysis showed that for patients who did not chew betel nuts and had low expression of ERCC1 were independent predictors for prolonged survival.</p> <p>Conclusions</p> <p>Our study suggest that a high expression of ERCC1 predict a poor response and survival to cisplatin-based IC followed by CCRT in patients with locally advanced unresectable HNSCC in betel nut chewing area.</p

Structure- and ligand-based virtual screening identifies new scaffolds for inhibitors of the oncoprotein MDM2

A major challenge in the field of ligand discovery is to identify chemically useful fragments that can be developed into inhibitors of specific protein-protein interactions. Low molecular weight fragments (with molecular weight less than 250 Da) are likely to bind weakly to a protein's surface. Here we use a new virtual screening procedure which uses a combination of similarity searching and docking to identify chemically tractable scaffolds that bind to the p53-interaction site of MDM2. The binding has been verified using capillary electrophoresis which has proven to be an excellent screening method for such small, weakly binding ligands

Designing an Adaptive Assisting Interface for Learning Virtual Filmmaking

International audienceIn this paper, we present an adaptive assisting interface for learning virtual filmmaking. The design of the system is based on the scaffolding theory, to provide timely guidance to the user in the form of visual and audio messages that are adapted to each person's skill level and performance. The system was developed on an existing virtual filmmaking setup. We conducted a study with 24 participants, who were asked to operate the film set with or without our adaptive assisting interface. Results suggest that our system can provide users with a better learning experience and positive knowledge harvest

Sequence variants of the aging gene CISD2 and the risk for Alzheimer's disease

Background/PurposeThe CISD2 gene has been related to life span control and mitochondrial dysfunction in animals. In addition, inhibition of mitochondrial enzymes due to an accumulation of beta-amyloid peptide has been related to Alzheimer's disease (AD). This study aimed to explore the association between sequence variants of the CISD2 gene and risk for AD, which has not been explored previously.MethodsThis was a case–control study involving a total of 276 patients with AD who were recruited from three teaching hospitals in Taiwan from 2007 to 2010; 460 controls were recruited from elderly individuals attending for health check-ups and volunteers in the hospital during the same period of time. All participants were aged 60 years or older. Two haplotype-tagging single nucleotide polymorphisms (htSNPs), rs223330 and rs223331, were selected from the CISD2 gene to test the association between their polymorphisms and the risk for dementia, and how ApoE ɛ4 status, sex, hypertension, and type 2 diabetes mellitus might modify this association.Resultsrs223330 variant carriage was not associated with risk for AD [TT versus CC: adjusted odds ratio (AOR) = 0.98, 95% confidence interval (CI) = 0.59–1.62; TC versus CC: AOR = 0.72, 95% CI = 0.47–1.11]. Similar findings were observed for rs223331 (AA versus TT: AOR = 1.12; AT versus TT: AOR = 0.99). In addition, hypertension significantly modified the association between rs223331 and risk for AD (p = 0.005).Three common haplotypes (with a frequency of 99.8%) were observed for CISD2. Common CISD2 haplotypes were not associated with the risk for AD.ConclusionOur findings suggested that CISD2 htSNPs are not associated with AD risk