Since their appearance at the end of the 19th century, traffic lights have been the primary mode of granting access to road intersections. Today, this centuries-old technology is challenged by advances in intelligent transportation, which are opening the way to new solutions built upon slot-based systems similar to those commonly used in aerial traffic: what we call Slot-based Intersections (SIs). Despite simulation-based evidence of the potential benefits of SIs, a comprehensive, analytical framework to compare their relative performance with traffic lights is still lacking. Here, we develop such a framework. We approach the problem in a novel way, by generalizing classical queuing theory. Having defined safety conditions, we characterize capacity and delay of SIs. In the 2-road crossing configuration, we provide a capacity-optimal SI management system. For arbitrary intersection configurations, near-optimal solutions are developed. Results theoretically show that transitioning from a traffic light system to SI has the potential of doubling capacity and significantly reducing delays. This suggests a reduction of non-linear dynamics induced by intersection bottlenecks, with positive impact on the road network. Such findings can provide transportation engineers and planners with crucial insights as they prepare to manage the transition towards a more intelligent transportation infrastructure in cities.
We describe a disease encompassing infantile-onset movement disorder (including severe parkinsonism and nonambulation), mood disturbance, autonomic instability, and developmental delay, and we describe evidence supporting its causation by a mutation in SLC18A2 (which encodes vesicular monoamine transporter 2 [VMAT2]). VMAT2 translocates dopamine and serotonin into synaptic vesicles and is essential for motor control, stable mood, and autonomic function. Treatment with levodopa was associated with worsening, whereas treatment with direct dopamine agonists was followed by immediate ambulation, near-complete correction of the movement disorder, and resumption of development.
High prevalence of physical inactivity contributes to adverse health outcomes. Active transportation (cycling or walking) is associated with better health outcomes, and bike-sharing programs can help communities increase use of active transportation.
Human-mediated dispersal is known as an important driver of long-distance dispersal for plants but underlying mechanisms have rarely been assessed. Road corridors function as routes of secondary dispersal for many plant species but the extent to which vehicles support this process remains unclear. In this paper we quantify dispersal distances and seed deposition of plant species moved over the ground by the slipstream of passing cars. We exposed marked seeds of four species on a section of road and drove a car along the road at a speed of 48 km/h. By tracking seeds we quantified movement parallel as well as lateral to the road, resulting dispersal kernels, and the effect of repeated vehicle passes. Median distances travelled by seeds along the road were about eight meters for species with wind dispersal morphologies and one meter for species without such adaptations. Airflow created by the car lifted seeds and resulted in longitudinal dispersal. Single seeds reached our maximum measuring distance of 45 m and for some species exceeded distances under primary dispersal. Mathematical models were fit to dispersal kernels. The incremental effect of passing vehicles on longitudinal dispersal decreased with increasing number of passes as seeds accumulated at road verges. We conclude that dispersal by vehicle airflow facilitates seed movement along roads and accumulation of seeds in roadside habitats. Dispersal by vehicle airflow can aid the spread of plant species and thus has wide implications for roadside ecology, invasion biology and nature conservation.
The two major modes of locomotion in humans, walking and running, may be regarded as a function of different speed (walking as slower and running as faster). Recent results using motor learning tasks in humans, as well as more direct evidence from animal models, advocate for independence in the neural control mechanisms underlying different locomotion tasks. In the current study, we investigated the possible independence of the neural mechanisms underlying human walking and running. Subjects were tested on a split-belt treadmill and adapted to walking or running on an asymmetrically driven treadmill surface. Despite the acquisition of asymmetrical movement patterns in the respective modes, the emergence of asymmetrical movement patterns in the subsequent trials was evident only within the same modes (walking after learning to walk and running after learning to run) and only partial in the opposite modes (walking after learning to run and running after learning to walk) (thus transferred only limitedly across the modes). Further, the storage of the acquired movement pattern in each mode was maintained independently of the opposite mode. Combined, these results provide indirect evidence for independence in the neural control mechanisms underlying the two locomotive modes.
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 3 years ago
The Pleistocene global dispersal of modern humans required the transit of arid and semiarid regions where the distribution of potable water provided a primary constraint on dispersal pathways. Here, we provide a spatially explicit continental-scale assessment of the opportunities for Pleistocene human occupation of Australia, the driest inhabited continent on Earth. We establish the location and connectedness of persistent water in the landscape using the Australian Water Observations from Space dataset combined with the distribution of small permanent water bodies (springs, gnammas, native wells, waterholes, and rockholes). Results demonstrate a high degree of directed landscape connectivity during wet periods and a high density of permanent water points widely but unevenly distributed across the continental interior. A connected network representing the least-cost distance between water bodies and graded according to terrain cost shows that 84% of archaeological sites >30,000 y old are within 20 km of modern permanent water. We further show that multiple, well-watered routes into the semiarid and arid continental interior were available throughout the period of early human occupation. Depletion of high-ranked resources over time in these paleohydrological corridors potentially drove a wave of dispersal farther along well-watered routes to patches with higher foraging returns.
Multidrug resistance driven by ABC membrane transporters is one of the major reasons for treatment failure in human malignancy. Some limited evidence has previously been reported on the cell cycle dependence of ABC transporter expression. However, it has never been demonstrated that the functional activity of these transporters correlates with the cell cycle position. Here, we studied the rate of intrinsic ABC transport in different phases of the cell cycle in cultured MCF-7 breast cancer cells. The rate was characterized in terms of the efflux kinetics from cells loaded with an ABC transporter substrate. As averaging the kinetics over a cell population could lead to errors, we studied kinetics of ABC transport at the single-cell level. We found that the rate of ABC transport in MCF-7 cells could be described by Michaelis-Menten kinetics with two classical parameters, V(max) and K(M). Each of these parameters showed similar unimodal distributions with different positions of maxima for cell subpopulations in the 2c and 4c states. Compared to the 2c cells, the 4c cells exhibited greater V(max) values, indicating a higher activity of transport. They also exhibited a greater V(max)/K(M) ratio, indicating a higher efficiency of transport. Our findings suggest that cell cycle-related modulation of MDR may need to be taken into account when designing chemotherapy regimens which include cytostatic agents.
- Drug metabolism and disposition: the biological fate of chemicals
- Published over 7 years ago
Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters, and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC(50) values of 1.3, 2.2 and 0.3 μM, respectively), silybin A (IC(50) values of 9.7, 2.7 and 4.5 μM, respectively), silybin B (IC(50) values of 8.5, 5.0 and 0.8 μM, respectively), and silychristin (IC(50) values of 9.0, 36.4 and 3.6 μM, respectively). Furthermore, silymarin, silybin A and silybin B (100 μM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC(50) values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Clinical investigations that achieve higher concentrations with either increased doses of silymarin or formulations with improved bioavailability may enhance the potential risk of DDIs with OATP substrates.
- Drug metabolism and disposition: the biological fate of chemicals
- Published over 7 years ago
Sutherlandia frutescens (ST) is a popular medicinal herb widely consumed in Africa by people living with HIV/AIDS. Concomitant use with antiretroviral drugs has generated concerns of herb-drug interaction. This study investigated the inhibitory effects of the crude extracts of ST on the major cytochrome P450 isozymes employing pooled human liver microsomes. Its effect on the metabolic clearance of midazolam using cryopreserved hepatocytes was also monitored. The potential of ST to inhibit human ATP-binding cassette (ABC) transporters (P-gp and BCRP) and the human organic anion transporting polypeptide (OATP1B1 and OATP1B3) activity was assessed using cell lines overexpressing the transporter proteins. ST showed inhibitory potency for CYP1A2 (IC(50) = 41.0 μg/mL), CYP2A6 (IC(50) = 160 μg/mL), CYP2B6 (IC(50) = 20.0 μg/mL), CYP2C8 (IC(50) = 22.4 μg/mL), CYP2C9 (IC(50) = 23.0 μg/mL), CYP2C19 (IC(50) = 35.9 μg/mL) and CYP3A4/5 (IC(50,) = 17.5 μg/mL [with midazolam1'-hydroxylation]; IC(50) = 28.3 μg/mL [with testosterone 6β-hydroxylation]). Time-dependent (irreversible) inhibition by ST was observed for CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min(-1)) under the conditions of this study. ST also delays the production of midazolam metabolites in the hepatocytes, decreasing its clearance by 40%. Further, ST inhibited P-gp (IC(50) = 324.8 μg/mL); OATP1B1 (IC(50) = 10.4 μg/mL, and of OATP1B3 (IC(50) = 6.6 μg/mL). The result indicates the potential for HDI between ST and the substrates of the affected enzymes, if sufficient in vivo concentration of ST is attained.
Issues of surfaces, e.g., inspired from beetle’s back, spider silk, cactus stem, etc., become the active area of research on designing novel materials in need of human beings to acquire fresh water resource from air. However, the design of materials on surface structure is little achieved on controlling of micro-scale drop transport in a long distance. Here, we report the ability of micro-drop transport in a long distance on a bioinspired Fibers with Gradient Spindle-knots (BFGS), which are fabricated by tilt angle dip-coating method. The micro-drop of ~0.25 μL transports in distance of ~5.00 mm, with velocity of 0.10-0.22 m s(-1) on BFGS. It is attributed to the multi-level cooperation of the release energy of drop coalescence along the gradient spindle-knots, in addition to capillary adhesion force and continuous difference of Laplace pressure, accordingly, water drops are driven to move fast directionally in a long distance on BFGS.