Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.
Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC)(1, 2). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the PI3K pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of HPV-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and non-canonical PIK3CA mutations were sensitive to an m-TOR/PI3K inhibitor (BEZ-235) in contrast to PIK3CA wildtype tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.
Gene therapy for cystic fibrosis (CF) lung disease requires efficient gene transfer to airway epithelial cells after intralumenal delivery. Most gene transfer vectors so far tested have not provided the efficiency required. Although human respiratory syncytial virus (RSV), a common respiratory virus, is known to infect the respiratory epithelium, the mechanism of infection and the epithelial cell type targeted by RSV have not been determined. We have utilized human primary airway epithelial cell cultures that generate a well-differentiated pseudostratified mucociliary epithelium to investigate whether RSV infects airway epithelium via the lumenal (apical) surface. A recombinant RSV expressing green fluorescent protein (rgRSV) infected epithelial cell cultures with high gene transfer efficiency when applied to the apical surface but not after basolateral inoculation. Analyses of the cell types infected by RSV revealed that lumenal columnar cells, specifically ciliated epithelial cells, were targeted by RSV and that cultures became susceptible to infection as they differentiated into a ciliated phenotype. In addition to infection of ciliated cells via the apical membrane, RSV was shed exclusively from the apical surface and spread to neighboring ciliated cells by the motion of the cilial beat. Gross histological examination of cultures infected with RSV revealed no evidence of obvious cytopathology, suggesting that RSV infection in the absence of an immune response can be tolerated for >3 months. Therefore, rgRSV efficiently transduced the airway epithelium via the lumenal surface and specifically targeted ciliated airway epithelial cells. Since rgRSV appears to breach the lumenal barriers encountered by other gene transfer vectors in the airway, this virus may be a good candidate for the development of a gene transfer vector for CF lung disease.Human respiratory syncytial virus (RSV) is the most important viral agent causing serious pediatric respiratory disease worldwide (5). RSV infection causes common-cold-like symptoms that progress to lower respiratory tract disease in 25 to 40% of infected infants and results in hospitalization for 0.1 to 1.0% of those infected. Almost everyone has been infected by RSV by 2 years of age. The immunity induced by RSV infection typically is incomplete, and reinfection is common, although subsequent infections are partially restricted and the disease severity is reduced (5).There is a relative lack of direct, detailed information on the characteristics of RSV infection, spread, and pathology in the upper and lower respiratory tract of humans. RSV infects the superficial layer of the respiratory epithelium and has the capacity to spread throughout the conducting airways. However, the details of RSV infection remain unclear, including whether there is a cell specificity to infection, the extent of virus infection and its relationship to disease manifestation and severity, the extent and cause of tissue damage, and whether the formation of syncytia that are so prominent in nonpola...
Halloysite is an alumosilicate tubular clay with a diameter of 50 nm, an inner lumen of 15 nm and a length of 600-900 nm. It is a natural biocompatible nanomaterial available in thousands of tons at low price, which makes it a good candidate for nanoarchitectural composites. The inner lumen of halloysite may be adjusted by etching to 20-30% of the tube volume and loading with functional agents (antioxidants, anticorrosion agents, flame-retardant agents, drugs, or proteins) allowing for formulations with sustained release tuned by the tube end-stoppers for hours and days. Clogging the tube ends in polymeric composites allows further extension of the release time. Thus, antioxidant-loaded halloysite doped into rubber enhances anti-aging properties for at least 12 months. The addition of 3-5 wt% of halloysite increases the strength of polymeric materials, and the possibility of the tube's orientation promises a gradient of properties. Halloysite nanotubes are a promising mesoporous media for catalytic nanoparticles that may be seeded on the tube surface or synthesized exclusively in the lumens, providing enhanced catalytic properties, especially at high temperatures. In vitro and in vivo studies on biological cells and worms indicate the safety of halloysite, and tests for efficient adsorption of mycotoxins in animals' stomachs are also carried out.
Healable, adhesive, wearable, and soft human-motion sensors for ultrasensitive human-machine interaction and healthcare monitoring are successfully assembled from conductive and human-friendly hybrid hydrogels with reliable self-healing capability and robust self-adhesiveness. The conductive, healable, and self-adhesive hybrid network hydrogels are prepared from the delicate conformal coating of conductive functionalized single-wall carbon nanotube (FSWCNT) networks by dynamic supramolecular cross-linking among FSWCNT, biocompatible polyvinyl alcohol, and polydopamine. They exhibit fast self-healing ability (within 2 s), high self-healing efficiency (99%), and robust adhesiveness, and can be assembled as healable, adhesive, and soft human-motion sensors with tunable conducting channels of pores for ions and framework for electrons for real time and accurate detection of both large-scale and tiny human activities (including bending and relaxing of fingers, walking, chewing, and pulse). Furthermore, the soft humanmotion sensors can be enabled to wirelessly monitor the human activities by coupling to a wireless transmitter. Additionally, the in vitro cytotoxicity results suggest that the hydrogels show no cytotoxicity and can facilitate cell attachment and proliferation. Thus, the healable, adhesive, wearable, and soft human-motion sensors have promising potential in various wearable, wireless, and soft electronics for human-machine interfaces, human activity monitoring, personal healthcare diagnosis, and therapy.
Forty years ago, high mobility group box 1 (HMGB1) was discovered in calf thymus and named according to its electrophoretic mobility in polyacrylamide gels. Now, we know that HMGB1 performs dual functions. Inside the cell, HMGB1 is a highly conserved chromosomal protein acting as a DNA chaperone. Outside of the cell, HMGB1 is a prototypical damage-associated molecular pattern, acting with cytokine, chemokine, and growth factor. During tumor development and in cancer therapy, HMGB1 has been reported to play paradoxical roles in promoting both cell survival and death by regulating multiple signaling pathways, including inflammation, immunity, genome stability, proliferation, metastasis, metabolism, apoptosis, and autophagy. Here, we review the current knowledge of both HMGB1’s oncogenic and tumor suppressive roles and the potential strategies that target HMGB1 for the prevention and treatment of cancer.
Herein, we report a de novo chemical design of supramolecular polymer materials (SPMs-1-3) by condensation polymerization, consisting of (i) soft polymeric chains (polytetramethylene glycol and tetraethylene glycol) and (ii) strong and reversible quadruple H-bonding cross-linkers (from 0 to 30 mol %). The former contributes to the formation of the soft domain of the SPMs, and the latter furnishes the SPMs with desirable mechanical properties, thereby producing soft, stretchable, yet tough elastomers. The resulting SPM-2 was observed to be highly stretchable (up to 17 000% strain), tough (fracture energy ∼30 000 J/m), and self-healing, which are highly desirable properties and are superior to previously reported elastomers and tough hydrogels. Furthermore, a gold, thin film electrode deposited on this SPM substrate retains its conductivity and combines high stretchability (∼400%), fracture/notch insensitivity, self-healing, and good interfacial adhesion with the gold film. Again, these properties are all highly complementary to commonly used polydimethylsiloxane-based thin film metal electrodes. Last, we proceed to demonstrate the practical utility of our fabricated electrode via both in vivo and in vitro measurements of electromyography signals. This fundamental understanding obtained from the investigation of these SPMs will facilitate the progress of intelligent soft materials and flexible electronics.
Lenz microphthalmia is inherited in an X-linked recessive pattern and comprises microphthalmia, mental retardation, and skeletal and other anomalies. Two loci associated with this syndrome, MAA (microphthalmia with associated anomalies) and MAA2, are situated respectively at Xq27-q28 (refs. 1,2) and Xp11.4-p21.2 (ref. 3). We identified a substitution, nt 254C→T; P85L, in BCOR (encoding BCL-6-interacting corepressor, BCOR 4 ) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus 3 . Oculofaciocardiodental syndrome (OFCD; OMIM 300166) is inherited in an X-linked dominant pattern with presumed male lethality and comprises microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities. Given their phenotypic overlap, we proposed that OFCD and MAA2-associated Lenz microphthalmia were allelic, and we found different frameshift, deletion and nonsense mutations in BCOR in seven families affected with OFCD. Like wild-type BCOR, BCOR P85L and an OFCDmutant form of BCOR can interact with BCL-6 and efficiently repress transcription. This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6. We cloned the zebrafish (Danio rerio) ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations of the eye, skeleton and central nervous system consistent with the human syndromes, confirming that BCOR is a key transcriptional regulator during early embryogenesis.We had previously localized MAA2 to a 10-Mb candidate region of Xp 3 . To identify the gene, we narrowed this region by excluding regions deleted in males with Xp deletions but without microphthalmia. Coriell cell line GM07947 is from a male with Duchenne muscular dystrophy, chronic granulomatous disease, McLeod phenotype and retinitis pigmentosa without microphthalmia 5 . Sequence-tagged site (STS) mapping confirmed previous data and oriented it to current genome maps. The deletion extended from DMD (telomeric) to between RPGR and OTC (centromeric; Fig. 1). The Coriell cell line GM10283 excluded two genes telomeric to DMD. This narrowed the critical region to ∼5 Mb, including 12 identified genes not known to be mutated in humans. One of these, DDX3, has an active Y homolog, and we therefore considered it unlikely to underlie a disorder with X-linked recessive inheritance. We sequenced the remaining 11 genes in members of the family in which MAA2 was originally identified. Ten of these genes showed no alterations, but we identified a missense change (nt 254C→T) in BCOR 4 that co-segregated with the disease phenotype (lod score of 2.46, above the threshold of 2.0 for X linkage 3 ). The corresponding residue of human BCOR, Pro85, is conserved in mouse, rat, chicken and pufferfish (Fig. 2), and we did not detect the nt 254C→T mutation among >450 control chromosomes. X-inactivation studies of peripheral blood leukocytes in two carriers of the mutation showed no ske...
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