Genome-wide conserved consensus transcription factor binding motifs are hyper-methylated.

BACKGROUND: DNA methylation can regulate gene expression by modulating the interaction between DNA and proteins or protein complexes. Conserved consensus motifs exist across the human genome ("predicted transcription factor binding sites": "predicted TFBS") but the large majority of these are proven by chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) not to be biological transcription factor binding sites ("empirical TFBS"). We hypothesize that DNA methylation at conserved consensus motifs prevents promiscuous or disorderly transcription factor binding. RESULTS: Using genome-wide methylation maps of the human heart and sperm, we found that all conserved consensus motifs as well as the subset of those that reside outside CpG islands have an aggregate profile of hyper-methylation. In contrast, empirical TFBS with conserved consensus motifs have a profile of hypo-methylation. 40% of empirical TFBS with conserved consensus motifs resided in CpG islands whereas only 7% of all conserved consensus motifs were in CpG islands. Finally we further identified a minority subset of TF whose profiles are either hypo-methylated or neutral at their respective conserved consensus motifs implicating that these TF may be responsible for establishing or maintaining an un-methylated DNA state, or whose binding is not regulated by DNA methylation. CONCLUSIONS: Our analysis supports the hypothesis that at least for a subset of TF, empirical binding to conserved consensus motifs genome-wide may be controlled by DNA methylation.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Enhanced Delivery of Rituximab Into Brain and Lymph Nodes Using Timed-Release Nanocapsules in Non-Human Primates.

Tumor metastasis into the central nervous system (CNS) and lymph nodes (LNs) is a major obstacle for effective therapies. Therapeutic monoclonal antibodies (mAb) have revolutionized tumor treatment; however, their efficacy for treating metastatic tumors-particularly, CNS and LN metastases-is poor due to inefficient penetration into the CNS and LNs following intravenous injection. We recently reported an effective delivery of mAb to the CNS by encapsulating the anti-CD20 mAb rituximab (RTX) within a thin shell of polymer that contains the analogs of choline and acetylcholine receptors. This encapsulated RTX, denoted as n-RTX, eliminated lymphoma cells systemically in a xenografted humanized mouse model using an immunodeficient mouse as a recipient of human hematopoietic stem/progenitor cells and fetal thymus more effectively than native RTX; importantly, n-RTX showed notable anti-tumor effect on CNS metastases which is unable to show by native RTX. As an important step toward future clinical translation of this technology, we further analyzed the properties of n-RTX in immunocompetent animals, rats, and non-human primates (NHPs). Our results show that a single intravenous injection of n-RTX resulted in 10-fold greater levels in the CNS and 2-3-fold greater levels in the LNs of RTX, respectively, than the injection of native RTX in both rats and NHPs. In addition, we demonstrate the enhanced delivery and efficient B-cell depletion in lymphoid organs of NHPs with n-RTX. Moreover, detailed hematological analysis and liver enzyme activity tests indicate n-RTX treatment is safe in NHPs. As this nanocapsule platform can be universally applied to other therapeutic mAbs, it holds great promise for extending mAb therapy to poorly accessible body compartments

Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice.

Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab. When the nanocapsules were functionalized with CXCL13-the ligand for the chemokine receptor CXCR5, which is frequently found on B-cell lymphoma-a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases

A Schwarz lemma for K\"ahler affine metrics and the canonical potential of a proper convex cone

This is an account of some aspects of the geometry of K\"ahler affine metrics based on considering them as smooth metric measure spaces and applying the comparison geometry of Bakry-Emery Ricci tensors. Such techniques yield a version for K\"ahler affine metrics of Yau's Schwarz lemma for volume forms. By a theorem of Cheng and Yau there is a canonical K\"ahler affine Einstein metric on a proper convex domain, and the Schwarz lemma gives a direct proof of its uniqueness up to homothety. The potential for this metric is a function canonically associated to the cone, characterized by the property that its level sets are hyperbolic affine spheres foliating the cone. It is shown that for an $n$-dimensional cone a rescaling of the canonical potential is an $n$-normal barrier function in the sense of interior point methods for conic programming. It is explained also how to construct from the canonical potential Monge-Amp\`ere metrics of both Riemannian and Lorentzian signatures, and a mean curvature zero conical Lagrangian submanifold of the flat para-K\"ahler space.Comment: Minor corrections. References adde

Micro- and macroscopic characterizations of the viscoelastic fracture of resin-based fibre composites

Micro- and macroscopic characterizations of the viscoelastic fracture of a unidirectional carbon-fibre-reinforced epoxy composite are presented. First, the micro-cracking behavior of the material is studied by the use of scanning electron microscopy; the in situ creep cracking process is observed and the crack propagation is measured. In order to obtain insight into the mechanisms of the observed creep cracking, macroscopic investigations were also carried out. Finite-element method simulations were carried out to calculate the stress distribution and the variation of stresses with time. A theoretical analysis of the orthotropy of viscoelastic fracture behavior of the material is also conducted

Development of social media addiction scale for COVID-19 pandemic (SMACOP)

The current COVID-19 pandemic and ‘new normal’ has resulted in much distress worldwide. Social media currently plays an essential role in information gathering. Thus, time spent on social media has increased drastically, further increasing the risk for internet-related addictions, such as social media addiction. This study aimed to develop a COVID-19-related measure of social media addiction based on the Bergen Social Media Addiction Scale (BSMAS) in order to aid in the identification and evaluation of at-risk individuals. Social Media Addiction Scale for COVID-19 Pandemic (SMACOP) was adapted from BSMAS to fit the context of COVID-19 and pilot tested on 20 individuals. A total of 80 participants were subsequently recruited through convenience sampling from the general public of a public university in Malaysia, comprising of patients’ family, visitors, or hospital staff. Construct validity was assessed using the Insomnia Severity Index (ISI), Generalized Anxiety Disorder 7 (GAD7) and Patient Health Questionnaire (PHQ9). A two-factor structure was found for SMACOP, comprising of the factors ‘Desire’ and ‘Distress’. SMACOP shows good internal consistency (α = 0.64) and validity. SMACOP scores were positively correlated with the PHQ9, GAD7, and ISI (p<.01). SMACOP is a psychometrically valid instrument with high internal consistency, which is especially useful during this time in assessing social media addiction in relevance to COVID-19

Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability

<p>Abstract</p> <p>Background</p> <p>Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene <it>eIF-5A2 </it>within the 3q26 region. Functional study has demonstrated the oncogenic role of <it>eIF-5A2 </it>in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of <it>eIF-5A2 </it>in an <it>eIF-5A2 </it>transgenic mouse model.</p> <p>Methods</p> <p>An <it>eIF-5A2 </it>transgenic mouse model was generated using human <it>eIF-5A2 </it>cDNA. The <it>eIF-5A2 </it>transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF) were isolated to further investigate molecular mechanism of <it>eIF-5A2 </it>in aging.</p> <p>Results</p> <p>Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in <it>eIF-5A2 </it>mice. Interestingly, we found that activation of <it>eIF-5A2 </it>repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF) cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (<it>p </it>< 0.05) resulted from an increase in the incidences of misaligned and lagging chromosomal materials, anaphase bridges, and micronuclei in the transgenic mice.</p> <p>Conclusion</p> <p>These observations suggest that <it>eIF-5A2 </it>mouse models could accelerate organismal aging by increasing chromosome instability.</p

Physical therapy for sleep apnea: a smartphone application for home-based physical therapy for patients with obstructive sleep apnea

PurposeIn this study, we described “PT for Sleep Apnea”, a smartphone application for home-based physical therapy of patients with Obstructive Sleep Apnea (OSA).MethodsThe application was created in a joint program between the University of Medicine and Pharmacy at Ho Chi Minh City (UMP), Vietnam, and National Cheng Kung University (NCKU), Taiwan. Exercises maneuvers were derived from the exercise program previously published by the partner group at National Cheng Kung University. They included exercises for upper airway and respiratory muscle training and general endurance training.ResultsThe application provides video and in-text tutorials for users to follow at home and a schedule function to assist the user in organizing the training program, which may improve the efficacy of home-based physical therapy in patients with Obstructive Sleep Apnea.ConclusionIn the future, our group plans to conduct a user study and randomized-controlled trials to investigate whether our application can benefit patients with OSA

Targeted gene therapy of nasopharyngeal cancer in vitro and in vivo by enhanced thymidine kinase expression driven by human TERT promoter and CMV enhancer

<p>Abstract</p> <p>Background/Aim</p> <p>To explore the therapeutic effects of thymidine kinase (TK) expressed by enhanced vector pGL3-basic- hTERTp-TK-EGFP-CMV driven by human telomerase reverse transcriptase promoter (hTERTp) as well as cytomegalovirus immediate early promoter enhancer (CMV).</p> <p>Materials/Methods</p> <p>Enhanced TK-EGFP expression was confirmed by fluorescent microscopy, real time PCR and telomerase activity. Its effects were examined by survival of tumor cells NPC 5-8F and MCF-7, index of xenograft implanted in nude mice and histology.</p> <p>Results</p> <p>Compared with non-enhanced vector pGL3-basic-TK-hTERTp-EGFP, TK expressed by the enhanced vector significantly decreased NPC 5-8F and MCF-7 cell survival rates after ganciclovir (GCV) treatment (p < 0.001) and tumor progress in nude mice with NPC xenograft and treated with GCV, without obvious toxicity to mouse liver and kidney.</p> <p>Conclusion</p> <p>The enhanced TK expression vector driven by hTERTp with CMV enhancer has brighter clinical potentials in nasopharyngeal carcinoma therapy than the non-enhanced vector.</p