Gene therapy to the gastrointestinal tract has remarkable potential for treating gastrointestinal disorders that currently lack effective treatments. Adeno-associated viral vectors (AAVs) have been extensively applied to the central nervous system, and have repeatedly demonstrated safety and efficacy in animal models. The enteric nervous system (ENS) represents a vast collection of neurons and glial cells that may also be subject to treatment by AAV, however little work has been conducted on AAV delivery to the ENS. Challenges for gastrointestinal gene therapy include identifying gene targets, optimizing gene delivery, and target cell selection. Researchers are now beginning to tackle the later of the two challenges with AAV, and the same AAV technology can be used to identify novel gene targets in the future. Continued efforts to understand AAV delivery and improve vector design are essential for therapeutic development. This review summarizes the current knowledge about AAV delivery to the ENS.
Acetate assimilation in C. reinhardtii leads to bicarbonate and CO2aq formation in heterotrophic growth condition. Bicarbonate and CO2aq thus formed under this condition remain in equilibrium with the action of carbonic anhydrases. Carbonic anhydrase catalyzes reversible hydration of carbon dioxide and dehydration of bicarbonate. In this article we report that the rapid exchange catalyzed by extracellular carbonic anhydrase causes a large magnetization (saturation) transfer effect on the 13C signal of bicarbonate at 161.01 ppm when the resonance of the carbon dioxide (aq) at 125.48 ppm is irradiated with RF pulses. In C. reinhardtii extracellular space the unidirectional, pseudo first-order rate constant of this exchange in the dehydration direction was determined to be 0.011 ± 0.005 sec-1. The presence of highly specific carbonic anhydrase inhibitor acetazolamide, was also shown to drastically attenuate the observed 13C magnetization transfer effect of the carbon dioxide–bicarbonate exchange in C. reinhardtii. We have demonstrated the utility of 13C saturation transfer for determining the exchange rate between bicarbonate and carbon dioxide catalyzed by extracellular carbonic anhydrase in C. reinhardtii extracellular space.This study for the first time reports the dehydration rate of bicarbonate to CO2 in live C. reinhardtii cells.
Macrophages contribute decisively to the initiation and progression of atherosclerosis. Although most studies conclude that plaque macrophages derive from circulating monocytes, there is growing evidence that vascular-resident smooth muscle cells (SMCs) may also differentiate into macrophages and contribute to the growing pool of foam cells in the atherosclerotic plaque. Understanding of SMC-to-macrophage differentiation has been clouded by inadequate fate-mapping studies and potentially inaccurate staining of SMC- or macrophage-specific markers. A new study published in Nature Medicine by Shankman et al., used a novel fate-mapping technique to label SMCs early in atherosclerosis and definitively assess their cellular fate throughout the progression of disease. The authors conclude that SMCs make up a striking number of cells in the atherosclerotic plaque, but lose several SMC-specific markers masking their inclusion in previous studies. Although this research illustrates the plasticity of SMCs and the importance of SMC retention in ameliorating atherosclerosis, it, unfortunately, does not confirm that SMCs differentiate into functional macrophages nor provide proof that SMC-to-macrophage differentiation is important for the progression of atherosclerosis.
Structural DNA nanotechnology explores various nanoscale structural and functional properties of DNA to develop probes at nanoscale for diverse applications. Three dimensional architectures based on DNA like various polyhedra, boxes, and DNA-based dendrimers, have raised particular interest in biomedical applications. Some of these DNA architectures have been recently explored as nano containers for functional molecules and as molecular scaffolds to site specifically display biological ligands. Such DNA nanostructures have been demonstrated to interact with cell-surface markers and trigger signalling pathways in biological systems via specific targets. These recent studies highlight the emerging potential of DNA devices in biomedical applications that could enable targeted delivery of molecular payloads within living systems.
High-throughput RNA and DNA sequencing approaches continue to yield informative data that provides insights into genomic patterns and variations that influence disease susceptibility and therapy outcome in cancer. The field is currently in need of high-throughput functional assays to test the impact of genetic variations identified by these next generation genomic techniques. Such methods are essential to identify mutations and genetic patterns that drive cancer or impact response to treatment. Since a majority of diseases associated with genome instability are driven by dysfunctional DNA repair pathways, there is an urgent need for assays that can effectively characterize mutations in DNA repair genes. This review outlines salient DNA repair pathways and functional repair assays described in literature that have clinical applications.
The CRISPR technology has recently received extensive attention from the research and medical community due to its remarkable genome-editing capacity. In particular, the therapeutic potential of translating the CRISPR technology into clinical interventions for various human diseases has brought bright hopes for patients around the world. In the current Commentary, I shall scrutinize recent advances in manipulating and improving the CRISPR technology for viral diseases and genetic disorders in humans. Key challenges to realize the full clinical potential of the CRISPR technology will also be discussed.
Until recently, a functional brown adipose tissue was thought to be restricted to rodents and human infants. The last eight years have seen a re-emergence in the presence and activity of brown adipose tissue in adult humans. This study by Shinoda and co-workers1 characterizes the cellular origins and molecular identity of adult human brown adipose tissue. Using RNA sequencing and genome wide expression analysis, the authors characterize that the clonally derived adipocytes isolated from brown fat of adult humans carry the genetic signature of recruitable thermogenic beige adipocytes. They further identify novel molecular markers that were highly enriched in the adult human brown adipocytes and rodent beige adipocytes. This study provides new approaches for BAT research and developing novel BAT targets.
Palbociclib has emerged as a novel inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). When activated by D-type cyclins, CDK4 and CDK6 phosphorylate proteins, the most important being retinoblastoma protein (RB1), which help to initiate the cellular transition from the G1 to the S phase. In hormone-receptor-positive breast cancer, cyclin D1 is overexpressed, thus driving the phosphorylation of RB1 by CDK4 and CDK6 and leading to increased cell proliferation. While most hormone-receptor-positive breast cancers are treated via endocrine therapy, some types are resistant to this treatment. Thus, by inhibiting CDK4 and CDK6 with extreme selectivity, palbociclib prevents the phosphorylation of RB1 and in turn arrests the cell in the G1 phase. In this research highlight, we will discuss a phase three trial paper from Turner et al. that assesses the efficacy of palbociclib, coupled with the estrogen receptor (ER) therapy fulvestrant, on patients with advanced hormone-receptor–positive, human epidermal growth factor receptor 2–negative breast cancer who had relapsed or progressed after being previously treated with endocrine therapy.
In this research, a novel way to examine the elastic strain effect on a platinum catalysis surface during oxygen reduction reaction (ORR) has been developed. A NiTi shape memory alloy was selected as substrate to provide both tensile and compressivestrain by using the nature of two-way shape memory effect for the first time. The experimental results clearly show that the compressive strain can enhance the ORR activity, while the tensile strain has the opposite effect during ORR.
In the recent federal-government-initiated accountability movement, teachers are one of the key stakeholders held accountable for student learning (Elliott & Hout, 2011). In this movement, we have also witnessed a renewed interest in performance-related pay (PRP) to incentivize teachers who significantly contribute to student learning (Podgursky & Springer, 2007; Liang & Akiba, 2011; Woessmann, 2011; Liang, 2013). Because student learning is measured largely by high-stakes tests, teachers are under pressure to “game the system and teach to the test for higher test scores instead of putting more effort into enhancing student understanding and cognitive skills” (Jacob & Levitt, 2003; Jacob, 2005; Liang & Akiba, 2015, p. 395). This challenges efforts to establish a connection between PRP and constructivist teaching practices that might not relate well to student test scores. In fact, some studies already indicated that PRP did not lead to improvement of instruction (Lavy, 2009; Glewwe et al., 2010).