Monitoring the fitness of antiviral-resistant influenza strains during an epidemic: a mathematical modelling study

postprin

Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment.

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events

Comparison of musculoskeletal strength and body composition of Hong Kong Chinese rugby players, dragon boat paddlers and controls

published_or_final_versio

Anisotropic step-flow growth and island growth of GaN(0001) by molecular beam epitaxy

GaN(0001) thin films are grown using radio frequency plasma assisted molecular beam epitaxy. By changing the growth temperature, anisotropic growth rate behavior is observed in both the step-flow growth mode and the 2D island growth mode. Tunneling scanning microscopy reveals, in the step-flow growth mode, strong influences from the growth anisotropy on the shape of the terrace edges, resulting in striking differences between hexagonal and cubic films. In the 2D nucleation growth mode, triangularly shaped islands are formed. The significance of growth anisotropy to growing high quality GaN films is discussed.published_or_final_versio

High throughput short read alignment via bi-directional BWT

The advancement of sequencing technologies has made it feasible for researchers to consider many highthroughput biological applications. A core step of these applications is to align an enormous amount of short reads to a reference genome. For example, to resequence a human genome, billions of reads of 35 bp are produced in 1-2 weeks, putting a lot of pressure of faster software for alignment. Based on existing indexing and pattern matching technologies, several short read alignment software have been developed recently. Yet this is still strong need to further improve the speed. In this paper, we show a new indexing data structure called bi-directional BWT, which allows us to build the fastest software for aligning short reads. When compared with existing software (Bowtie is the best), our software is at least 3 times faster for finding unique best alignments, and 25 times faster for finding all possible alignments. We believe that bi-directional BWT is an interesting data structure on its own and could be applied to other pattern matching problems. Availability: http://www.bio5.cs.hku.hk:8080/P2BWT, where two human genomes are indexed for alignment. © 2009 IEEE.published_or_final_versionThe IEEE International Conference on Bioinformatics and Biomedicine (BIBM 2009), Washington, DC., 1-4 November 2009. In Proceedings of BIBM, 2009, p. 31-3

p38 MAPK, microglial signaling, and neuropathic pain

Accumulating evidence over last several years indicates an important role of microglial cells in the pathogenesis of neuropathic pain. Signal transduction in microglia under chronic pain states has begun to be revealed. We will review the evidence that p38 MAPK is activated in spinal microglia after nerve injury and contributes importantly to neuropathic pain development and maintenance. We will discuss the upstream mechanisms causing p38 activation in spinal microglia after nerve injury. We will also discuss the downstream mechanisms by which p38 produces inflammatory mediators. Taken together, current data suggest that p38 plays a critical role in microglial signaling under neuropathic pain conditions and represents a valuable therapeutic target for neuropathic pain management

NRF2 Mediates Therapeutic Resistance to Chemoradiation in Colorectal Cancer through a Metabolic Switch

Radiation resistance is a significant clinical problem in rectal cancer treatment, the mechanisms of which are poorly understood. NRF2 signalling is known to contribute to chemo/radioresistance in some cancers, but its role in therapeutic resistance in colorectal cancer (CRC) is unexplored. Using siRNA and CRiSPR/Cas9 isogenic CRC cell lines, we investigated the effect of the knockdown and upregulation of the NRF2 pathway on chemo-radiosensitivity. Poly (A) enriched RNA sequencing and geneset enrichment analysis (GSEA) were carried out on both sensitive and resistant cell models for mechanistic insights. Finally, a cohort of rectal patient samples was profiled to understand the clinical relevance of NRF2 signalling. Radioresistant cell lines were significantly radiosensitised by siRNA knockdown (SW1463, SER10 1.22, ANOVA p < 0.0001; HT55, SER10 1.17, ANOVA p < 0.01), but not the (already) radiosensitive HCT116. The constitutive activation of NRF2 via a CRISPR Cas9 NFE2L2 mutation, E79K, induced radioresistance in HCT116 (SER10 0.71, ANOVA, p < 0.0001). GSEA demonstrated significant opposing metabolic dependencies in NRF2 signalling, specifically, the downregulation of amino acid and protein synthesis with low levels of NRF2 and upregulation with over expression. In a clinical cohort of 127 rectal patients, using a validated mRNA signature, higher baseline NRF2 signalling was associated with incomplete responses to radiation higher final neoadjuvant rectal (NAR) score (OR 1.34, 95% C.I. 1.01–1.80, LRT p-value = 0.023), where high NAR indicates poor radiation response and poor long-term prognosis. This is the first demonstration of NRF2-mediated radiation resistance in colorectal cancer. NRF2 appears to regulate crucial metabolic pathways, which could be exploited for therapeutic interventions

On the complexity of color-avoiding site and bond percolation

The mathematical analysis of robustness and error-tolerance of complex networks has been in the center of research interest. On the other hand, little work has been done when the attack-tolerance of the vertices or edges are not independent but certain classes of vertices or edges share a mutual vulnerability. In this study, we consider a graph and we assign colors to the vertices or edges, where the color-classes correspond to the shared vulnerabilities. An important problem is to find robustly connected vertex sets: nodes that remain connected to each other by paths providing any type of error (i.e. erasing any vertices or edges of the given color). This is also known as color-avoiding percolation. In this paper, we study various possible modeling approaches of shared vulnerabilities, we analyze the computational complexity of finding the robustly (color-avoiding) connected components. We find that the presented approaches differ significantly regarding their complexity.Comment: 14 page

Fabrication of Large Area Periodic Nanostructures Using Nanosphere Photolithography

Large area periodic nanostructures exhibit unique optical and electronic properties and have found many applications, such as photonic band-gap materials, high dense data storage, and photonic devices. We have developed a maskless photolithography method—Nanosphere Photolithography (NSP)—to produce a large area of uniform nanopatterns in the photoresist utilizing the silica micro-spheres to focus UV light. Here, we will extend the idea to fabricate metallic nanostructures using the NSP method. We produced large areas of periodic uniform nanohole array perforated in different metallic films, such as gold and aluminum. The diameters of these nanoholes are much smaller than the wavelength of UV light used and they are very uniformly distributed. The method introduced here inherently has both the advantages of photolithography and self-assembled methods. Besides, it also generates very uniform repetitive nanopatterns because the focused beam waist is almost unchanged with different sphere sizes

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer

We hypothesise that the NRF2 transcription factor would act a biomarker of poor prognosis in colorectal cancer. We derived and validated an mRNA based metagene signature of NRF2 signalling and validated it in 1360 patients from 4 different datasets as an independent biomarker of poor prognosis. This is a novel insight into the molecular signalling of colorectal cancer. Background: NRF2 over activity confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights. Methods: Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway activity using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms. Results: 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 95% C.I 1.2–2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086–1.416, p = 0.001; GSE87211 HR=1.431, 95% C.I 1.06–1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% C.I 1.04–1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was particularly enriched in Consensus Molecular Subtype (CMS) 4. Conclusion: For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study