Mechanobiological stimulation in organ-on-a-chip systems reduces hepatic drug metabolic capacity in favor of regenerative specialization.

Hepatic physiology depends on the liver's complex structural composition which among others, provides high oxygen supply rates, locally differential oxygen tension, endothelial paracrine signaling, as well as residual hemodynamic shear stress to resident hepatocytes. While functional improvements were shown by implementing these factors into hepatic culture systems, direct cause-effect relationships are often not well characterized-obfuscating their individual contribution in more complex microphysiological systems. By comparing increasingly complex hepatic in vitro culture systems that gradually implement these parameters, we investigate the influence of the cellular microenvironment to overall hepatic functionality in pharmacological applications. Here, hepatocytes were modulated in terms of oxygen tension and supplementation, endothelial coculture, and exposure to fluid shear stress delineated from oxygen influx. Results from transcriptomic and metabolomic evaluation indicate that particularly oxygen supply rates are critical to enhance cellular functionality-with cellular drug metabolism remaining comparable to physiological conditions after prolonged static culture. Endothelial signaling was found to be a major contributor to differential phenotype formation known as metabolic zonation, indicated by WNT pathway activity. Lastly, oxygen-delineated shear stress was identified to direct cellular fate towards increased hepatic plasticity and regenerative phenotypes at the cost of drug metabolic functionality - in line with regenerative effects observed in vivo. With these results, we provide a systematic evaluation of critical parameters and their impact in hepatic systems. Given their adherence to physiological effects in vivo, this highlights the importance of their implementation in biomimetic devices, such as organ-on-a-chip systems. Considering recent advances in basic liver biology, direct translation of physiological structures into in vitro models is a promising strategy to expand the capabilities of pharmacological models.

Tailoring the carbon nanostructures grown on the surface of Ni-Al bimetallic nanoparticles in the gas phase.

A gas-phase, one-step method for producing various aerosol carbon nanostructures is described. The carbon nanostructures can be selectively tailored with either straight, coiled, or sea urchin-like structures by controlling the size of Ni-Al bimetallic nanoparticles and the reaction temperature. The carbon nanostructures were grown using both conventional spray pyrolysis and thermal chemical vapor deposition. Bimetallic nanoparticles with catalytic Ni (guest) and non-catalytic Al (host) matrix were reacted with acetylene and hydrogen gases. At the processing temperature range of 650-800 °C, high concentration straight carbon nanotubes (S-CNTs) with a small amount of coiled carbon nanotubes (C-CNTs) can be grown on the surface of seeded bimetallic nanoparticle size <100 nm, resulting from consumption of the melting Al matrix sites; sea urchin-like carbon nanotubes (SU-CNTs) of small diameter (∼10±4 nm) can be grown on the bimetallic nanoparticle size >100 nm, resulting from the significant size reduction of the available Ni sites due to thermal expansion of molten Al matrix sites without consumption of Al matrix. However, at the processing temperature range of 500-650 °C, C-CNTs can be grown on the bimetallic nanoparticle size <100 nm due to the presence of Al matrix in the bimetallic nanoparticles; SU-CNTs of large diameter (∼60±13 nm) can also be grown on the bimetallic nanoparticle size >100 nm due to the isolation of Ni sites in the Al matrix.

Synthesis of length-controlled aerosol carbon nanotubes and their dispersion stability in aqueous solution.

A one-step method combining spray pyrolysis and thermal chemical vapor deposition (CVD) processes was developed to grow hybrid carbon nanotube (CNT)-bimetallic composite particles. Nickel, aluminum, and acetylene were used as the catalytic site, noncatalytic matrix, and hydrocarbon source, respectively. The bimetallic particles (i.e., Al-Ni) were spray pyrolized and subsequently passed through thermal CVD. During the thermal CVD, the catalytic decomposition of acetylene occurred on the free-floating bimetallic particles so that sea urchin-like CNTs were radially grown. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses revealed the CNTs to have a uniform diameter of approximately 10 +/- 2 nm. The length of the CNTs was controlled by varying the residence time of the bimetallic nanoparticles with a length of 200-1000 nm. After nitric acid treatment, the CNTs were released by melting the bimetallic particles. The resulting CNTs were then dispersed in an aqueous solution to examine the effect of the length of CNTs on their dispersion stability, which is a critical issue for the stability and repeatability of the heat transfer performance in nanofluids. Ultraviolet-visible (UV-vis) spectrometer analysis showed that shorter CNTs were less stable than the longer CNTs due to the higher mobility-induced agglomeration of the shorter CNTs.

Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. Recent work in rodent models of ALS has shown that insulin-like growth factor-1 (IGF-1) slows disease progression when delivered at disease onset. However, IGF-1's mechanism of action along the neuromuscular axis remains unclear. In this study, symptomatic ALS mice received IGF-1 through stereotaxic injection of an IGF-1-expressing viral vector to the deep cerebellar nuclei (DCN), a region of the cerebellum with extensive brain stem and spinal cord connections. We found that delivery of IGF-1 to the central nervous system (CNS) reduced ALS neuropathology, improved muscle strength, and significantly extended life span in ALS mice. To explore the mechanism of action of IGF-1, we used a newly developed in vitro model of ALS. We demonstrate that IGF-1 is potently neuroprotective and attenuates glial cell-mediated release of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO). Our results show that delivering IGF-1 to the CNS is sufficient to delay disease progression in a mouse model of familial ALS and demonstrate for the first time that IGF-1 attenuates the pathological activity of non-neuronal cells that contribute to disease progression. Our findings highlight an innovative approach for delivering IGF-1 to the CNS.

Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive paralysis arising from the premature death of motor neurons. An inherited form is caused by a dominant mutation in the ubiquitously expressed superoxide dismutase (SOD1). SOD1 mutant expression within motor neurons is a determinant of onset and early disease, and mutant accumulation within microglia accelerates disease progression. Muscle also is a likely primary source for toxicity, because retraction of motor axons from synaptic connections to muscle is among the earliest presymptomatic events. To test involvement of muscle in ALS, viral delivery of transcription-mediated siRNA is shown to suppress mutant SOD1 accumulation within muscle alone but to be insufficient to maintain grip strength, whereas delivery to both motor neurons and muscle is sufficient. Use of a deletable mutant gene to diminish mutant SOD1 from muscle did not affect onset or survival. Finally, follistatin expression encoded by adeno-associated virus chronically inhibited myostatin and produced sustained increases in muscle mass, myofiber number, and fiber diameter, but these increases did not affect survival. Thus, SOD1-mutant-mediated damage within muscles is not a significant contributor to non-cell-autonomous pathogenesis in ALS, and enhancing muscle mass and strength provides no benefit in slowing disease onset or progression.

A selected, annotated list of materials that support the development of policies designed to reduce racial and ethnic health disparities.

Research documents the existence of racial and ethnic health disparities. As a result, policy makers are seeking to address these disparities. This list is a starting point for building or updating a collection that supports this policy development process. It is written for health policy librarians and researchers and includes annotated recommendations for books, periodicals, government publications, and Websites. Entries for print publications are primarily from 1998 to 2003.

Percutaneous laryngeal collagen augmentation for treatment of parkinsonian hypophonia.

OBJECTIVE: Our goal was to determine whether percutaneous laryngeal collagen augmentation improves hypophonia in parkinsonian patients. STUDY DESIGN AND SETTING: A retrospective review of 18 patients was performed. Patients and/or caretakers were called on the telephone and asked about their response to the procedure, if any. Videostroboscopic examinations for all patients were reviewed. RESULTS: Of 18 patients, 11 (61%) reported improvement in their hypophonia for a period of at least 2 months. Five of 7 patients without improvement were relatively aphonic both before and after the procedure. Five of 7 patients without improvement had severe dysphagia, which in 3 necessitated gastrostomy tube placement. Four of 7 patients without improvement were not ambulatory at the time of the procedure. CONCLUSIONS: Percutaneous laryngeal collagen augmentation is an effective treatment for parkinsonian hypophonia in a majority of patients. Patients with advanced neurologic disease with aphonia, difficulty with speech initiation, dysphagia, or ambulatory difficulty are less likely to respond to this procedure and should be so informed.