| 1. |
- Deng, Tingzhi, et al.
(författare)
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Hippocampal Transcriptome-Wide Association Study Reveals Correlations Between Impaired Glutamatergic Synapse Pathway and Age-Related Hearing Loss in BXD-Recombinant Inbred Mice
- 2021
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Age-related hearing loss (ARHL) is associated with cognitive dysfunction; however, the detailed underlying mechanisms remain unclear. The aim of this study is to investigate the potential underlying mechanism with a system genetics approach. A transcriptome-wide association study was performed on aged (12-32 months old) BXD mice strains. The hippocampus gene expression was obtained from 56 BXD strains, and the hearing acuity was assessed from 54 BXD strains. Further correlation analysis identified a total of 1,435 hearing-related genes in the hippocampus (p < 0.05). Pathway analysis of these genes indicated that the impaired glutamatergic synapse pathway is involved in ARHL (p = 0.0038). Further gene co-expression analysis showed that the expression level of glutamine synthetase (Gls), which is significantly correlated with ARHL (n = 26, r = -0.46, p = 0.0193), is a crucial regulator in glutamatergic synapse pathway and associated with learning and memory behavior. In this study, we present the first systematic evaluation of hippocampus gene expression pattern associated with ARHL, learning, and memory behavior. Our results provide novel potential molecular mechanisms involved in ARHL and cognitive dysfunction association.
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| 2. |
- Abramson, Alex, et al.
(författare)
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A luminal unfolding microneedle injector for oral delivery of macromolecules
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:10, s. 1512-
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Tidskriftsartikel (refereegranskat)abstract
- Insulin and other injectable biologic drugs have transformed the treatment of patients suffering from diabetes(1,2), yet patients and healthcare providers often prefer to use and prescribe less effective orally dosed medications(3-5). Compared with subcutaneously administered drugs, oral formulations create less patient discomfort(4), show greater chemical stability at high temperatures(6), and do not generate biohazardous needle waste(7). An oral dosage form for biologic medications is ideal; however, macromolecule drugs are not readily absorbed into the bloodstream through the gastrointestinal tract(8). We developed an ingestible capsule, termed the luminal unfolding microneedle injector, which allows for the oral delivery of biologic drugs by rapidly propelling dissolvable drug-loaded microneedles into intestinal tissue using a set of unfolding arms. During ex vivo human and in vivo swine studies, the device consistently delivered the microneedles to the tissue without causing complete thickness perforations. Using insulin as a model drug, we showed that, when actuated, the luminal unfolding microneedle injector provided a faster pharmacokinetic uptake profile and a systemic uptake > 10% of that of a subcutaneous injection over a 4-h sampling period. With the ability to load a multitude of microneedle formulations, the device can serve as a platform to orally deliver therapeutic doses of macromolecule drugs.
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| 3. |
- Abramson, Alex, et al.
(författare)
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Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors
- 2021
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 40:1, s. 103-109
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Tidskriftsartikel (refereegranskat)abstract
- Oral administration provides a simple and non-invasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics. Here we present an orally dosed liquid auto-injector capable of delivering up to 4-mg doses of a bioavailable drug with the rapid pharmacokinetics of an injection, reaching an absolute bioavailability of up to 80% and a maximum plasma drug concentration within 30 min after dosing. This approach improves dosing efficiencies and pharmacokinetics an order of magnitude over our previously designed injector capsules and up to two orders of magnitude over clinically available and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for delivery of clinically relevant doses of four commonly injected medications, including adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system.
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| 4. |
- Caffarel-Salvador, Ester, et al.
(författare)
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A microneedle platform for buccal macromolecule delivery
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.
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| 5. |
- Wang, Hongya, et al.
(författare)
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Comparing mineral magnetic properties of sediments in two reservoirs in "strongly" and "mildly" eroded regions on the Guizhou Plateau, southwest China: A tool for inferring differences in sediment sources and soil erosion
- 2011
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Ingår i: Geomorphology. - : Elsevier BV. - 0169-555X. ; 130:3-4, s. 255-271
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Tidskriftsartikel (refereegranskat)abstract
- Shibanqiao Reservoir (0.24 km(2)) and Xiaohe Reservoir (0.28 km(2)) have catchments of 6.00 km(2) and 22.69 km(2), respectively. They essentially represent "strongly eroded" (Shibanqiao) and "mildly eroded" (Xiaohe) regions in Guizhou Plateau, southwestern China. Sediment cores were retrieved from the two reservoirs and soils were also sampled from their catchments. Mineral magnetic measurements were performed on the sediments and soils, and the particle-size analysis of selected sediment cores and soil profiles were also made. SIRM versus chi if was used to compare sediment and soil samples. In addition, correlations between percentages of different particle-size fractions and magnetic parameters/ratios of sediment samples were also checked. These results revealed differences in sediment sources and soil erosion in these two representative catchments. The sediments in Shibanqiao Reservoir are derived from both the topsoil and subsoil. When erosion is relatively weak, it is limited to the topsoil and preferentially transports the relatively finer magnetic grains into the reservoir, which may imply rain splash and/or sheet erosion. In this relatively steep catchment, stronger erosional forces are capable of not only moving relatively coarser ferrimagnetic grains from the topsoil, but also incising the subsoil and moving anti-ferromagnetic minerals into the reservoir, which seems to hint at not only sheet-wash but also rill and gully erosion. As there are no stable streams nor channel networks developed in this mountainous catchment, contributions from river-bank erosion to sediment yield are almost negligible. The sediments in Xiaohe Reservoir, which has a lower relief, are predominately derived from topsoil erosion. Here, erosion is concentrated to the topsoil and preferentially transports the relatively fine magnetic grains into the reservoir when erosional forces are weak. However, even when erosional forces increase in this relatively flat catchment, erosion is still restricted to the topsoil. Thus, relatively coarser ferrimagnetic grains from the topsoil are transported to the reservoir, but the subsoil remains undisturbed and there are no significant changes in the proportion of anti-ferromagnetic minerals in the sediments. Consequently, only sheet-washing occurs even when erosion is intensifying in this hilly plain catchment. In general, the more effective erosion in the Shibanqiao Catchment is probably due to its steeper topography than Xiaohe Catchment, although higher and more seasonal rainfalls and lower percentages of woodlands may also contribute to the differences in susceptibility to erosional forces. (C) 2011 Elsevier B.V. All rights reserved.
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