Hyporheic exchange, or the exchange of water and solutes between surface and subsurface water at the sediment‐water interface, regulates water quality and biogeochemical cycle in aquatic ecosystems. ...Vegetation, which is ubiquitous in nature, is known to impact hyporheic exchange; yet how vegetation impacts hyporheic exchange remains to be characterized. Here, we show that at the same spatially and temporally‐averaged flow velocity U $U$, vegetation increases the rate of hyporheic exchange by a factor of four. By tracking the movement of fluorescent dye in a flume with the refractive‐index‐matched sediment and translucent vegetation dowels, we demonstrate that the vegetation‐induced hyporheic exchange can be characterized by an effective hyporheic exchange velocity, VH ${V}_{H}$. We further demonstrate that VH ${V}_{H}$ correlates with the total near‐bed turbulent kinetic energy kt ${k}_{t}$ rather than U $U$, when kt<6×10−4m2/s2 ${k}_{t}< 6\times {10}^{-4}\,{\mathrm{m}}^{2}/{\mathrm{s}}^{2}$, indicating that turbulent kinetic energy is a better metric than flow velocity for predicting hyporheic exchange in regions with vegetation.
Plain Language Summary
The exchange of contaminants and nutrients between surface and subsurface water in the hyporheic zone of rivers and wetlands controls water quality as well as the metabolism of benthic microbes and the associated biogeochemical cycle. Vegetation, which is ubiquitous in aquatic ecosystems, has been found to affect the surface‐subsurface exchange and as such impact water quality and stream biogeochemical cycle. However, how vegetation impacts this exchange remains unclear, making it difficult to predict the contaminant transport and biogeochemical cycle in streams, lakes, and coastal areas with vegetation. In this study, we directly visualized the release of a fluorescent dye from the transparent sediment into the surface water in a water‐recirculating tank filled with translucent vegetation. We discovered that vegetation can significantly increase the exchange in the hyporheic zone. Furthermore, we proposed a model to predict the impacts of vegetation on hyporheic exchange. We believe that this finding will help improve predictions of contaminant transport and biogeochemical cycle in streams and other aquatic ecosystems. The results of this study will also help ecologists design stream restoration projects that use vegetation to increase the retention and degradation of contaminants in sediment.
Key Points
Emergent vegetation increases the exchange of water and solutes between surface and subsurface water in the hyporheic zone
The release of solute from the sediment bed can be approximated by a mass transfer equation with an effective hyporheic exchange velocity
The impacts of vegetation on the hyporheic exchange velocity can be characterized by the near‐bed turbulent kinetic energy kt
Magnetic particle imaging is an emerging tomographic technique with the potential for simultaneous high-resolution, high-sensitivity, and real-time imaging. Magnetic particle imaging is based on the ...unique behavior of superparamagnetic iron oxide nanoparticles modeled by the Langevin theory, with the ability to track and quantify nanoparticle concentrations without tissue background noise. It is a promising new imaging technique for multiple applications, including vascular and perfusion imaging, oncology imaging, cell tracking, inflammation imaging, and trauma imaging. In particular, many neuroimaging applications may be enabled and enhanced with magnetic particle imaging. In this review, we will provide an overview of magnetic particle imaging principles and implementation, current applications, promising neuroimaging applications, and practical considerations.
Recently, rhenium disulfide (ReS sub(2)) monolayers were experimentally extracted by conventional mechanical exfoliation technique from as-grown ReS sub(2) crystals. Unlike the well-known members of ...transition metal dichalcogenides (TMDs), ReS sub(2) crystallizes in a stable distorted-1T structure and lacks an indirect to direct gap crossover. Here we present an experimental and theoretical study of the formation, energetics, and stability of the most prominent lattice defects in monolayer ReS sub(2). Experimentally, irradiation with 3-MeV He super(+2) ions was used to break the strong covalent bonds in ReS sub(2) flakes. Photoluminescence measurements showed that the luminescence from monolayers is mostly unchanged after highly energetic alpha particle irradiation. In order to understand the energetics of possible vacancies in ReS sub(2) we performed systematic first-principles calculations. Our calculations revealed that the formation of a single sulfur vacancy has the lowest formation energy in both Re and S rich conditions and a random distribution of such defects are energetically more preferable. Sulfur point defects do not result in any spin polarization whereas the creation of Re-containing point defects induce magnetization with a net magnetic moment of 1-3 mu sub(B). Experimentally observed easy formation of sulfur vacancies is in good agreement with first-principles calculations.
One of the most effective ways in which regulatory agencies communicate with sponsors and guide drug development is through the issuance of guidances or guidelines. These can be issued domestically ...in a given region such as the United States by the Food and Drug Administration (FDA) or internationally through the International Conference on Harmonization. Currently, there are over 400 final or draft guidances that can be found through the FDA website. The development of guidances proceeds through a process known as Good Guidance Practices, which is intended to assure that there is an appropriate level of meaningful public participation in the development of guidance. In the past 10 years, clinical pharmacology guidances covering important areas have been issued, including pharmacokinetic data in patients with renal and hepatic impairment, dose‐response studies, and drug‐drug interactions.
Clinical Pharmacology & Therapeutics (2007) 81, 298–304. doi:10.1038/sj.clpt.6100054
BCL2 and MCL1 are commonly expressed prosurvival (antiapoptotic) proteins in hematologic cancers and play important roles in their biology either through dysregulation or by virtue of intrinsic ...importance to the cell-of-origin of the malignancy. A new class of small-molecule anticancer drugs, BH3 mimetics, now enable specific targeting of these proteins in patients. BH3 mimetics act by inhibiting the prosurvival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors that permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other antineoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single-agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3 mimetics are better suited to limited duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3 mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma, and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several nonhematologic tissues.
This phase II, open-label study evaluated the efficacy and safety of erlotinib as second-line therapy in non-small-cell lung cancer (NSCLC) patients with brain metastases (BM).
Forty-eight patients ...aged 18–75 years with Eastern Cooperative Oncology Group performance status 0–2, confirmed adenocarcinoma or activating epidermal growth factor receptor (EGFR) mutation-positive NSCLC, and asymptomatic BM without extracranial progressive disease after first-line platinum-doublet chemotherapy were recruited. Treatment comprised erlotinib 150 mg/day. The primary end point was progression-free survival (PFS) determined by RECIST.
The median PFS was 10.1 months 95% confidence interval (CI) 7.1–12.3 for intracranial progression and 9.7 months (95% CI 2.5–17.8) for intracranial and systemic progression. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease 15.2 months (95% CI 8.3–22.2) versus 4.4 months (95% CI 0.0–11.6); P = 0.02. The median overall survival was 18.9 months (95% CI 14.4–23.4); 6-month and 1-year survival rates were 85% and 73%, respectively. Overall response rate was 58.3%. Most common adverse events were rash (77.1%), paronychia (20.8%), hyperbilirubinemia (16.7%), and diarrhea (14.6%); these were predominantly of grade 1/2.
Single-agent erlotinib was active and well tolerated in NSCLC patients with BM. Further studies are warranted.
Summary Objective To study the effects of oral glucosamine sulfate on the development of osteoarthritis (OA) and to examine concomitant changes in the nociceptive behavior of rats. Methods OA was ...induced in Wistar rats by anterior cruciate ligament transection (ACLT) of the right knee; the left knee was untreated. The OA + glucosamine group received oral glucosamine sulfate (250 mg/kg/day) in a 2-g wafer once a day for 10 consecutive weeks starting at week 5 after ACLT. The OA group was treated as above with 2-g wafers (placebo). The control group of naïve rats received 2-g wafers only. The glucosamine alone group comprised naïve rats receiving glucosamine sulfate only. Nociceptive behavior (mechanical allodynia and weight-bearing distribution of hind paws) during OA development was analyzed pre- and 3, 6, 9, 12, 15, and 18 weeks post-ACLT. Macroscopic and histologic studies were then performed on the cartilage and synovia. Immunohistochemical analysis was performed to examine the effect of glucosamine on expression of mitogen-activated protein kinases (MAPKs) in the articular cartilage chondrocytes. Results OA rats receiving glucosamine showed a significantly lower degree of cartilage degeneration than the rats receiving placebo. Glucosamine treatment also suppressed synovitis. Mechanical allodynia and weight-bearing distribution studies showed significant improvement in the OA + glucosamine group as compared to the OA group. Moreover, glucosamine attenuated p38 and c-Jun N-terminal kinase (JNK) but increased extracellular signal-regulated kinase 1/2 (ERK) expression in OA-affected cartilage. Conclusion Our results indicate that treatment with oral glucosamine sulfate in a rat OA model (1) attenuates the development of OA, (2) concomitantly reduces nociception, and (3) modulates chondrocyte metabolism, possibly through inhibition of cell p38 and JNK and increase of ERK expression.
Using Cluster data, we investigate the electric structure of a dipolarization front (DF) – the ion inertial length (c/ωpi) scale boundary in the Earth's magnetotail formed at the front edge of an ...earthward propagating flow with reconnected magnetic flux. We estimate the current density and the electron pressure gradient throughout the DF by both single‐spacecraft and multi‐spacecraft methods. Comparison of the results from the two methods shows that the single‐spacecraft analysis, which is capable of resolving the detailed structure of the boundary, can be applied for the DF we study. Based on this, we use the current density and the electron pressure gradient from the single‐spacecraft method to investigate which terms in the generalized Ohm's law balance the electric field throughout the DF. We find that there is an electric field at ion inertia scale directed normal to the DF; it has a duskward component at the dusk flank of DF but a dawnward component at the dawn flank of DF. This electric field is balanced by the Hall (j × B/ne) and electron pressure gradient (∇ Pe/ne) terms at the DF, with the Hall term being dominant. Outside the narrow DF region, however, the electric field is balanced by the convection (Vi × B) term, meaning the frozen‐in condition for ions is broken only at the DF itself. In the reference frame moving with the DF the tangential electric field is almost zero, indicating there is no flow of plasma across the DF and that the DF is a tangential discontinuity. The normal electric field at the DF constitutes a potential drop of ∼1 keV, which may reflect and accelerate the surrounding ions.
Key Points
We calculate E at DF using single‐ and four‐ spacecraft methods
Normal E is balanced by the Hall (dominant) and pressure gradient terms
At dawn flank, E is dawnward; At dusk flank, E is duskward
Drug interactions due to efflux transport inhibition at the blood–brain barrier (BBB) have been receiving increasing scrutiny because of the theoretical possibility of adverse central nervous system ...(CNS) effects identified in preclinical studies. In this review, evidence from pharmacokinetic, pharmacodynamic, imaging, pharmacogenetic, and pharmacovigilance studies, along with drug safety reports, is presented supporting a low probability of modulating transporters at the human BBB by currently marketed drugs.
Clinical Pharmacology & Therapeutics (2013); 94 1, 80–94. doi:10.1038/clpt.2013.34
Physiologically based pharmacokinetic (PBPK) approaches that incorporate the developmental physiology and ontogeny of cytochrome P450 (CYP) enzymes may have value in the design of pediatric trials. ...Four recent submissions to the US Food and Drug Administration (FDA) incorporated different PBPK applications to pediatric drug development. Further testing of PBPK models for three drugs showed that these models generally underpredicted drug clearance. PBPK modeling may have potential for improving pediatric trials through the learn‐and‐confirm approaches utilized in current regulatory submissions.
Clinical Pharmacology & Therapeutics (2012); 91 5, 926–931. doi:10.1038/clpt.2012.19
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