Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial stress response (ISRmt), which is controlled by mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21.

The iPlant Collaborative (iPlant) is a United States National Science Foundation (NSF) funded project that aims to create an innovative, comprehensive, and foundational cyberinfrastructure in support of plant biology research (PSCIC, 2006). iPlant is developing cyberinfrastructure that uniquely enables scientists throughout the diverse fields that comprise plant biology to address Grand Challenges in new ways, to stimulate and facilitate cross-disciplinary research, to promote biology and computer science research interactions, and to train the next generation of scientists on the use of cyberinfrastructure in research and education. Meeting humanity's projected demands for agricultural and forest products and the expectation that natural ecosystems be managed sustainably will require synergies from the application of information technologies. The iPlant cyberinfrastructure design is based on an unprecedented period of research community input, and leverages developments in high-performance computing, data storage, and cyberinfrastructure for the physical sciences. iPlant is an open-source project with application programming interfaces that allow the community to extend the infrastructure to meet its needs. iPlant is sponsoring community-driven workshops addressing specific scientific questions via analysis tool integration and hypothesis testing. These workshops teach researchers how to add bioinformatics tools and/or datasets into the iPlant cyberinfrastructure enabling plant scientists to perform complex analyses on large datasets without the need to master the command-line or high-performance computational services.

The magnetic nanoparticle has emerged as a potential multifunctional clinical tool that can provide cancer cell detection by magnetic resonance imaging (MRI) contrast enhancement as well as targeted cancer cell therapy. A major barrier in the use of nanotechnology for brain tumor applications is the difficulty in delivering nanoparticles to intracranial tumors. Iron oxide nanoparticles (IONP; 10 nm in core size) conjugated to a purified antibody that selectively binds to the epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIII) present on human glioblastoma multiforme (GBM) cells were used for therapeutic targeting and MRI contrast enhancement of experimental glioblastoma, both in vitro and in vivo, after convectionenhanced delivery (CED). A significant decrease in glioblastoma cell survival was observed after nanoparticle treatment and no toxicity was observed with treatment of human astrocytes (P < 0.001). Lower EGFR phosphorylation was found in glioblastoma cells after EGFRvIIIAb-IONP treatment. Apoptosis was determined to be the mode of cell death after treatment of GBM cells and glioblastoma stem cell-containing neurospheres with EGFRvIIIAb-IONPs. MRI-guided CED of EGFRvIIIAb-IONPs allowed for the initial distribution of magnetic nanoparticles within or adjacent to intracranial human xenograft tumors and continued dispersion days later. A significant increase in animal survival was found after CED of magnetic nanoparticles (P < 0.01) in mice implanted with highly tumorigenic glioblastoma xenografts (U87ΔEGFRvIII). IONPs conjugated to an antibody specific to the EGFRvIII deletion mutant constitutively expressed by human glioblastoma tumors can provide selective MRI contrast enhancement of tumor cells and targeted therapy of infiltrative glioblastoma cells after CED. Cancer Res; 70(15); 6303-12. ©2010 AACR.

The tumor stroma in human cancers significantly limits the delivery of therapeutic agents into cancer cells. To develop an effective therapeutic approach overcoming the physical barrier of the stroma, we engineered urokinase plasminogen activator receptor (uPAR)-targeted magnetic iron oxide nanoparticles (IONPs) carrying gemcitabine (Gem) as a chemotherapy drug for targeted delivery into uPAR-expressing tumor and stromal cells. The uPAR-targeted nanoparticle construct, ATF-IONP-Gem, was prepared by conjugating IONPs with the amino-terminal fragment (ATF) peptide of the receptor-binding domain of uPA, a natural ligand of uPAR, and Gem via a lysosomally cleavable tetrapeptide linker. These theranostic nanoparticles enable intracellular release of Gem following receptor-mediated endocytosis of ATF-IONP-Gem into tumor cells, and also allow in vivo magnetic resonance imaging (MRI) of tumors. Our results demonstrated the pH- and lysosomal enzyme-dependent release of gemcitabine, preventing the drug from enzymatic degradation. Systemic administrations of ATF-IONP-Gem significantly inhibited the growth of orthotopic human pancreatic cancer xenografts in nude mice. With MRI contrast enhancement by IONPs, we detected the presence of IONPs in the residual tumor lesions following the treatment, suggesting the possibility of monitoring drug delivery and assessing drug resistant tumors by MRI. The theranostic ATF-IONP-Gem nanoparticle has great potential for the development of targeted therapeutic and imaging approaches that are capable of overcoming the tumor stromal barrier, thus enhancing the therapeutic effect of nanoparticle drugs on pancreatic cancers.

Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISR mt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy ISR mt progresses in temporal stages, and development from early to chronic is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISR mt (ATF5, mitochondrial one-carbon cycle, FGF21, GDF15). The local progression to 2 nd metabolic ISR mt-stage (ATF3, ATF4, glucose uptake, serine biosynthesis, transsulfuration) is FGF21-dependent. Mitochondrial unfolded protein response marks the 3 rd ISR mtstage of failing tissue. Systemically, FGF21 drives weight-loss, glucose-preference and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.

An increasing utilization of flexible healthcare electronics and biomedicine-related therapeutic materials urges the development of multifunctional wearable/flexible smart fabrics for personal therapy and health management. However, it is currently a challenge to fabricate multifunctional and on-body healthcare electronic devices with reliable mechanical flexibility, excellent breathability, and self-controllable joule heating effects. Here, we fabricate a multifunctional MXene-based smart fabric by depositing 2D Ti3C2T x nanosheets onto cellulose fiber nonwoven fabric via special MXene–cellulose fiber interactions. Such multifunctional fabrics exhibit sensitive and reversible humidity response upon H2O-induced swelling/contraction of channels between the MXene interlayers, enabling wearable respiration monitoring application. Besides, it can also serve as a low-voltage thermotherapy platform due to its fast and stable electro-thermal response. Interestingly, water molecular extraction induces electrical response upon heating, i.e., functioning as a temperature alarm, which allows for real-time temperature monitoring for thermotherapy platform without low-temperature burn risk. Furthermore, metal-like conductivity of MXene renders the fabric an excellent Joule heating effect, which can moderately kill bacteria surrounding the wound in bacteria-infected wound healing therapy. This work introduces a multifunctional smart flexible fabric suitable for next-generation wearable electronic devices for mobile healthcare and personal medical therapy.

The poor delivery efficiency remains a major challenge in nanomaterial based tumor targeted imaging and drug delivery. This work demonstrated a strategy to improve nanoparticle delivery and intratumoral distribution using a sub-5 nm (3.5 nm core size) ultrafine iron oxide nanoparticles (uIONPs) that can easily extravasate from the tumor vasculature and readily diffuse into the tumor tissue compared to iron oxide nanoparticles (IONP) with larger sizes, followed by self-assembling in the acidic tumor interstitial space to limit their re-entering the circulation. By combining enhanced extravasation and reduced intravasation, improved delivery and tumor retention of nanoparticles are achieved. Multi-photon imaging of mice bearing orthotopic tumors co-injected with fluorescent dye labeled nanoparticles with different sizes showed that uIONPs exhibited more efficient extravasation out of tumor vessels and penetrated deeper into the tumor than larger sized IONP counterparts. Moreover, in vivo magnetic resonance imaging (MRI) revealed that uIONPs exhibited “bright” T1 contrast when dispersed in the tumor vasculature and peripheral area at 1 hour after intravenous administration, followed by emerging “dark” T2 contrast in the tumor after 24 hours. Observed T1–T2 contrast switch indicated that uIONPs single-dispersed in blood with T1 contrast may self-assemble into larger clusters with T2 contrast after entering the tumor interstitial space. Improved passive targeting and intratumoral delivery along with increased tumor retention of uIONP are due to both easy extravasation into the tumor when single-dispersed and restricting intravasation back into circulation after forming clusters, thus, exerting the enhanced permeability and retention (EPR) effect for nanoparticle delivery to tumors.

BACKGROUND AND PURPOSE:Mild cognitive impairment (MCI) is a risk factor for Alzheimer disease and can be difficult to diagnose because of the subtlety of symptoms. This study attempted to examine gray matter (GM) and white matter (WM) changes with cortical thickness analysis and diffusion tensor imaging (DTI) in patients with MCI and demographically matched comparison subjects to test these measurements as possible imaging markers for diagnosis.