A ‘passive’ surveillance strategy offers a continuous monitoring

A ‘passive’ surveillance strategy offers a continuous monitoring of disease occurrence within a population

by reporting notifiable diseases on a case-by-case basis. Passive surveillance is advantageous because it occurs continuously, and it requires few resources. In contrast, ‘active’ surveillance is a proactive strategy for laboratories to disseminate information about notifiable diseases. While the latter method is more costly and labor intensive, it tends to provide a more complete estimate of disease frequency. A robust surveillance system should prioritize data collection, recognising the need for cooperation through a ‘One Health’ agenda (Fooks, 2007, WHO, 2008 and Fisman and Laupland, 2010). An effective system should also be characterized by standardisation and decentralisation, emphasizing locally-based efforts, and by coordination, interpretation and integration of different learn more approaches. find more To support standardization, the OIE has proposed a pathway to sustainably improve the compliance of veterinary services, setting international standards as a continuous process of reflection and improvement. Its key components

are performance, vision and strategy. By following this pathway, veterinary services will acquire the knowledge and skills needed to control and prevent rabies (Murray and Aviso, 2012). Where the technology is available, surveillance data can be transferred to a real-time, web-based reporting and communication system, using a Geographic Information Systems (GIS) linked to internet-based mapping tools (Rupprecht et al., 2006b). Reporting systems, such as the Rabies Bulletin Europe (RBE) (Freuling et al., 2012) and the OIE World Animal Health Information diglyceride System (WAHID) interface, depend on consistent

disease reporting, backed up by confirmatory laboratory diagnosis by participating countries, both of which are often lacking. Their dependence on different sectors for the development and reporting of case data demonstrates the need for a multi-sectoral, integrated and inter-disciplinary approach (Fig. 2). Reliable systematic surveillance of human rabies deaths and animal prevalence at the national level (Fig. 3) would markedly improve knowledge and response to rabies, and is urgently needed. More than 30 years ago, the global eradication of smallpox demonstrated that well-supported surveillance campaigns are essential to reduce and potentially eliminate an infectious disease (Fenner et al., 1988). Fortunately, a great deal of progress has been made against rabies. Animal management, including public education, responsible dog ownership and vaccination strategies, have been identified as the keystone of modern control programs. Using this model, the connection between rabies in dogs and humans has been clearly demonstrated through the successful elimination of canine rabies from Western Europe and parts of the Americas (WHO, 2010).

We entered task (reading vs proofreading) and experiment (Experi

We entered task (reading vs. proofreading) and experiment (Experiment 1 vs. Experiment 2) as fixed effects in the LMMs. The global reading measures confirmed the results of the accuracy analyses: The proofreading task was more difficult

than the reading task, and this difference was more pronounced in the second experiment. Both measures revealed significant effects of task (TSRT: b = 814.8, t = 7.99; WPM: b = −53.18, t = −9.74), with the proofreading task leading to less efficient (slower) reading (MTSRT = 2986 ms; MWPM = 299 in Experiment 1 MTSRT = 4320 ms; MWPM = 226 in Experiment 2) than the reading for comprehension task (MTSRT = 2699 ms; MWPM = 327 in Experiment 1 MTSRT = 2970 ms; MWPM = 304 in Experiment 2). Both measures also revealed a significant selleck effect of experiment Selleck Fasudil (TSRT: b = 801.7, t = 4.00; WPM: b = −47.84, t = −3.06), with less efficient reading in the second experiment than

in the first experiment. More importantly, there was a significant interaction in both measures (TSRT: b = 1063.1, t = 5.23; WPM: b = −49.85, t = −4.62), with the effect of task (reading vs. proofreading) larger in the second experiment (when proofreading involved checking for wrong words) than in the first experiment (when proofreading involved checking for nonwords). To assess how task demands change processing of the target words themselves (i.e., the only word that differed between tasks and between experiments in the proofreading task) we analyzed local reading measures (the same as mentioned above) on the filler Fenbendazole trials; Table 10, Table 11 and Table 12. All analyses revealed a significant effect of task (for all fixation time measures, all ts > 12; for all fixation probability measures, all ps < .001) with longer reading times on and higher probabilities of fixating and regressing into or out of the target in the proofreading task than the reading task. There

were significant differences between experiments in gaze duration and total time (both ts > 2.09), as well as the probability of regressing out of and into the target (both ps < .001), but not for any of the other fixation time measures (all ts < 1.77) or the probability of fixating the target (p = .32). Most important for our purposes were tests for interactions between task and experiment. Analyses of fixation time measures revealed significant but qualitatively different interactions between task and experiment for early and late reading measures. There were significant interactions for early reading measures (first fixation duration: b = −19.24, t = 2.25; single fixation duration: b = −31.18, t = 2.78; gaze duration: b = −45.41, t = 3.18) with a larger increase in reading time in the proofreading block when checking for nonword errors (Experiment 1) than when checking for wrong word errors (Experiment 2; see Fig. 1).

As scientists from diverse disciplines improve the ability to qua

As scientists from diverse disciplines improve the ability to quantify rates and magnitudes of diverse fluxes, it becomes increasingly clear that the majority of landscape change occurs during relatively short periods of time and that some portions of the

landscape are much more dynamic than other portions, as illustrated by several examples. Biogeochemists describe a short period of time with disproportionately high reaction rates relative to longer intervening time periods as a hot moment, and a small area with disproportionately high reaction rates relative Selleckchem EGFR inhibitor to the surroundings as a hot spot (McClain et al., 2003). Numerous examples of inequalities in time and space exist in the geomorphic literature. More than 75% of the long-term sediment flux from mountain rivers in Taiwan occurs less than 1% of the time, during typhoon-generated floods (Kao and Milliman, 2008). Approximately 50% of the suspended sediment discharged by rivers of the Western Transverse Ranges of California, USA comes from the 10% of the basin underlain by weakly consolidated bedrock (Warrick and Mertes, 2009). Somewhere between 17% and 35% of the total particulate organic carbon flux to the world’s oceans comes from high-standing islands in

the southwest Pacific, which constitute only about 3% of Earth’s landmass (Lyons et al., 2002). One-third of the total amount of stream energy generated by the Tapi River of India during the monsoon season is expended click here on the day of the peak flood (Kale and Hire, 2007). Three-quarters of the carbon

stored in dead wood and floodplain sediments along headwater mountain stream networks Phosphatidylinositol diacylglycerol-lyase in the Colorado Front Range is stored in one-quarter of the total length of the stream network (Wohl et al., 2012). Because not all moments in time or spots on a landscape are of equal importance, effective understanding and management of critical zone environments requires knowledge of how, when, and where fluxes occur. Particularly dynamic portions of a landscape, such as riparian zones, may be disproportionately important in providing ecosystem services, for example, and relatively brief natural disturbances, such as floods, may be disproportionately important in ensuring reproductive success of fish populations. Recognition of inequalities also implies that concepts and process-response models based on average conditions should not be uncritically applied to all landscapes and ecosystems. Geomorphologists are used to thinking about thresholds. Use of the term grew rapidly following Schumm’s seminal 1973 paper “Geomorphic thresholds and complex response of drainage systems,” although thinking about landscape change in terms of thresholds was implicit prior to this paper, as Schumm acknowledged.

, 2009) and was supported by both the quasi-stable sea level in t

, 2009) and was supported by both the quasi-stable sea level in the Black Sea since the mid Holocene (Giosan et al., 2006a and Giosan et al., 2006b) and the drastic increase in discharge over the last 1000–2000 years (Giosan et al., Selleck Vemurafenib 2012). Second, delta fringe depocenters supporting delta lobe development are associated only with the mouths of major distributaries, but their volume is influenced by both sediment discharge and mouth morphodynamics. Lobes develop and are maintained not only via repartitioning most of the sediment

load to a single distributary but also by trapping of fluvial and marine sediments at the wave-dominated mouths of small discharge distributaries and periodically releasing them downcoast (Giosan et al., 2005). In this way, multiple lobes with different morphologies can coexist, abandonment of wave-dominated lobes is delayed and, by extension, the intensity ZD6474 of coastal erosion is minimized. River delta restoration as defined by Paola et al. (2011) “involves diverting sediment and water from major channels into adjoining drowned areas, where the sediment can build new land and provide

a platform for regenerating wetland ecosystems.” Such strategies are being currently discussed for partial restoration of the Mississippi delta, because the fluvial sediment load there is already lower than what is necessary to offset the already lost land ( Turner, 1997, Blum and Roberts, 2009 and Blum and Roberts, 2012). The decline in fluvial sediment load on the Mississippi Phloretin combined with the isolation of the delta plain by artificial levees and enhanced subsidence have led to enormous losses of wetland, but capture of some fluvial sediment that is now lost at sea (e.g., Falcini et al., 2012) is envisioned via controlled river releases during floods and/or diversions

( Day et al., 1995, Day et al., 2009, Day et al., 2012 and Nittrouer et al., 2012). Strategies are designed to maximize the capture of bedload, which is the primary material for new land build up ( Allison and Meselhe, 2010 and Nittrouer et al., 2012) and they include deep outlet channels and diversions after meander bends where lift-off of bed sand increases. Mass balance modeling for the Mississippi delta indicates that between a fourth and a half of the estimated land loss could be counteracted by capturing the available fluvial sediment load ( Kim et al., 2009). Sand is indeed needed to nucleate new land in submerged environments, but enhancing the input of fine sediments to deltaic wetlands should in principle be an efficient way to maintain the delta plain that is largely above sea level because fine suspended sediments make up the great bulk of the sediment load in large rivers (e.g., 98–95%; Milliman and Farnsworth, 2011).

Mousterian assemblages in Eurasia show greater variation through

Mousterian assemblages in Eurasia show greater variation through space and time, but are still relatively static compared to the rapid technological changes that characterize the technologies developed by AMH. After the beginning of the Middle Stone Age in Africa about 250,000 years ago, there is evidence for a rapid and accelerating tempo of technological change among AMH populations, beginning with blade-based technologies, more sophisticated bifacial tools, the first appearance of microlithic tools, as well as formal bone,

ground stone, weaving, ceramic, and other technologies. Progressing through the Upper Paleolithic, Mesolithic, Neolithic, Bronze, and Iron ages, technological change among AMH often occurred very rapidly, marked by nearly constant PS-341 in vivo innovation and ingenuity. Selleckchem BMS387032 Such innovations include the first widespread evidence for art and personal ornamentation, tailored clothing, boats, harpoons, the domestication of the dog, and much more. By 10,000 years ago, humans were domesticating a variety of plants and animals independently in various parts of the world (see Goudie, 2000 and Smith and Zeder, 2014), a process of experimentation and genetic manipulation that led to a fundamental

realignment in the relationship of humans to their local environments. With better technologies and increasingly productive methods of food production (combined with foraging), human populations expanded and developed increasingly complex social, economic, and political institutions, again almost simultaneously

in multiple parts of the world. These processes fueled additional innovation and ever-greater human impacts on local and regional ecosystems. As early states evolved into kingdoms, empires, and nations, the stage was set for broader social and economic networks, leading to exchange of goods and ideas, exploration, competition, cooperation, and conflict, the results of which still play out today in a globalized but highly competitive world. Etofibrate Since the 1960s, archeologists have debated the nearly simultaneous appearance of domestication, agriculture, and complex cultures in widely dispersed areas around the world, areas with very different ecologies as well as human colonization and demographic histories. Traditional explanations for this Holocene ‘revolution’ have relied on environmental change, population pressure, and growing resource stress as the primary causes for such widespread yet similar developmental trajectories among human societies around the world (e.g., Binford, 1968, Cohen, 1977, Cohen, 2009 and Hayden, 1981; see also Richerson et al., 2001). All these stimuli may have contributed to cultural developments in various regions, but today, armed with much more information about the very different colonization, environmental, and developmental histories of human societies in various areas, such explanations no longer seem adequate.

Akt is also a key antiapoptotic effector of cellular growth facto

Akt is also a key antiapoptotic effector of cellular growth factors [35]. PI3K activation by growth factors leads to Akt activation, which is an important player in survival pathway [36]. Some studies have shown

that Akt suppresses apoptosis signaling via BCL2 induction [27], and p-p53 inhibition through MDM2 activation [37]. Previously, KRG was shown to upregulate PI3K/Akt signaling and to inhibit apoptosis via Bortezomib in vitro the regulation of BCL2 and caspase-3 expression, thus protecting endothelial cells from starvation [38]. Moreover, Panax notoginseng saponins inhibit ischemia-induced apoptosis by stimulating PI3K/Akt signaling in cardiomyocytes [39]. However, the mechanism by which KRG activates PI3K/Akt signal via ER-β under oxidative stress in brain cells has been unclear until now. In this study,

we demonstrated that KRG increases PI3K/Akt signaling via upregulation of ER-β, thus inhibiting apoptosis through p-p53 and caspase-3 downregulation and BCL2 induction in oxidatively stressed brain cells. Excitotoxicity SCH727965 molecular weight is the pathological process caused by neurotransmitter glutamate such as n-methyl-d-aspartate (NMDA) and kainic acid [40]. These excitotoxins bind to glutamate receptor and result in increase of intracellular Ca2+. Subsequently, overload of intracellular Ca2+ stimulates activation of enzymes comprising calpains, which are the ubiquitously expressed family of Ca2+-dependent proteases Alanine-glyoxylate transaminase [40]; thus these enzymes can damage

cellular structures such as cytoskeleton, and are important for apoptosis and necrosis. Estrogen induced ER-α inhibited excitotoxicity via downregulating calpain expression [41]. In addition, ER-β play an important role in estrogenic neuroprotection against NMDA-induced excitotoxicity [42]. Red ginseng extract was reported to have neuroprotective activity against kainic acid-induced excitotoxicity in vitro and in vivo by inhibition of ROS level [40]. Moreover, ginsenoside Rg3 exhibited neuroprotection against homocysteine-induced excitotoxicity via inhibition of homocysteine-mediated NMDA receptor activation [43]. Our results showed that KRG increases ER-β expression and provides ER-β mediated-neuroprotection. Taken together, KRG-induced ER-β seems to play some role in protection against excitotoxicity. However, further studies are necessary for elucidation of the underlying mechanism. Ginsenosides are structurally similar to glucocorticoids or estrogens. In agreement, ginsenosides Re and Rg1 are functional ligands of the glucocorticoid receptor, whereas ginsenosides Rb1 and Rh1 are functional ligands of the ER [44]. Ginseng was also shown to activate ER in breast cancer cells in vitro but not in vivo [19]. Previously, we found that the ER-α expression was not affected in vitro by oxidative stress nor by KRG treatment, thus ERα would not be predicted to play a major role in oxidative stress in the brain [17].

Data for WSM in 2002–2013

Data for WSM in 2002–2013 ZD1839 supplier including controlled water discharge and suspended sediment concentration, released water and sediment volume, scoured

sediment volume, and water storage (Table 5), were also incorporated to analyze impacts of the WSM on the delivery of Huanghe material to the sea. The Yellow River Water Conservancy Commission (YRCC) provided most of the datasets used in this study. Other data are obtained from the Yellow River Sediment Bulletin and River Sediment Bulletin of China, published by the Ministry of Water Resources, China. Satellite images (HJ-1 CCD) are also used to observe changes of water in the Xiaolangdi reservoir and the lower reaches before and during operation of the Water-Sediment Modulation. The HJ-1 CCD satellite data are available at http://www.cresda.com/n16/index.html. We calculated the number of days for different daily-average water discharges recorded

at Huayuankou and Lijin stations in different time periods, to explore the impacts of dams on flow regulation and control of flood peaks. Given that the Sanmenxia reservoir has a minor effect on flow regulation, we divided the study time period 1950–2011 into four stages: 1950–1968, 1969–1986, 1987–1999 and 2000–2011, corresponding with the construction of the Longyanxia, Liujiaxia, and Xiaolangdi reservoirs. We Natural Product Library research buy also calculate the difference in water discharge at Huayuankou and Lijin to estimate the water consumption favored by flow regulation through dams. Cumulative infilling of sediment in the Sanmenxia and Xiaolangdi reservoirs

was computed based on the sediment infilling data that were released annually from the Yellow River Sediment Bulletin. Influence of the WSM on Huanghe water and sediment transport to the sea was also assessed through comparison of hydrologic data before and after the operation of the WSM. General effects of dams on the Huanghe include flow regulation, sediment entrapment, control of peak flows, and changes in suspended Florfenicol sediment concentration and grain size. We link the impacts of dams with decreasing Huanghe water and sediment discharges to the sea. The causes and impacts of decreased Huanghe water and sediment discharges have been well documented (Yang et al., 1998, Xu, 2003, Wang et al., 2006, Wang et al., 2007 and Wang et al., 2010) and are reviewed below. In addition, we outline the annual WSM, which has played a significant role in regulating water and sediment discharge to the sea since 2002. The four large dams on the Huanghe modulate river flow by storing floodwater in wet seasons and releasing it in dry seasons. Results of the data analysis reveal that the ratio of average daily discharge during non-flood seasons to the average daily discharge during flood seasons at Huayuankou station increases progressively from 34.2% during 1950–1968 to 67.8% during 2000–2004 (Table 2).

, 2010, Kaltenrieder et al , 2010 and Valsecchi et al , 2010) Fo

, 2010, Kaltenrieder et al., 2010 and Valsecchi et al., 2010). For the first time the high values of the indicators for anthropogenic activity no PLX4032 in vivo longer coincided with high fire frequencies ( Conedera and Tinner, 2000). During the Middle Ages the approach to fire by the Alpine population reveals contrasting aspects. As a general rule, fire use was banished from the landscape being a threat to buildings, protection

forests ( Brang et al., 2006), timber plantations and crops, as deducible from the numerous local bylaws dating back to the 13th century ( Conedera and Krebs, 2010). On the other hand, no prohibition or even obligation of pastoral burning in selected common pastures existed in many local communities ( Conedera et al., 2007). Besides a number of bylaws, evidence remaining of the second fire epoch can be found

in the many place names referring to the use of fire to clear brushwood to improve pasture-land or to eliminate trees (Italian brüsada; old French arsis, arsin, arselle; old German swenden and riuten; or present Swiss German schwendi) ( Sereni, 1981 and Conedera et al., 2007), as well as in the historical literature, e.g., Schmitthenner (1923), Schneiter (1970), Sereni (1981), Lutz (2002), Bürgi and Stuber (2003), Goldammer and Bruce (2004), Forni (2011). As a consequence, charcoal influx records slightly increase during the Middle Ages at the majority of sites investigated ( Gobet et al., 2003, not Blarquez et al., 2010, Kaltenrieder et al., 2010 and Valsecchi et al., 2010). Later, in the 18th and 19th R428 purchase centuries, the shortage of timber resources, forest privatization and development of the timber industry required increased fire control, and the prohibition of agro-pastoral use of fire (Conedera et al., 2004a and Conedera and Krebs, 2010), similarly to what Pyne (2001) reported for other areas. As a consequence, charcoal influx records decreased in Modern Times reaching

constant lower values in the 20th century in comparison with previous periods, excluding Roman Times (Tinner et al., 1999, Carcaillet et al., 2009, Blarquez et al., 2010, Colombaroli et al., 2010, Kaltenrieder et al., 2010 and Valsecchi et al., 2010). Similarly to other geographical areas, fire control policies have been strengthened during the second half of the 20th century also in the Alps, determining an overall decrease in the area burnt in the Alpine region (Conedera et al., 2004b, Zumbrunnen et al., 2010 and Pezzatti et al., 2013). Fig. 4 shows the decrease in yearly burnt area from the end of the 20th century which characterized most Alpine areas. This is particular evident in sub-regions with the highest burnt area such as Piemonte, Ticino and Friuli Venezia Giulia in Western, Central and Eastern Alps, respectively (Fig. 5). The current fire regime is characterized mainly by autumn-winter and early-spring slope-driven anthropogenic surface fires (Pezzatti et al.

, 1997 and Tobin et al , 2002) and osm-9 is needed to induce calc

, 1997 and Tobin et al., 2002) and osm-9 is needed to induce calcium transients to multiple noxious stimuli ( Hilliard et al., 2005). (The contribution of ocr-2 to nose touch-evoked calcium transients Anti-infection Compound Library has not been tested.) These data and the

recent demonstration that optogenetic stimulation of ASH works in osm-9 mutants ( Guo et al., 2009) support the proposal that OSM-9 is a candidate subunit of an MeT in ASH ( Colbert et al., 1997, Hilliard et al., 2005 and Tobin et al., 2002). In this study, we combined in vivo whole-cell patch-clamp recording and genetic dissection to deconstruct mechanoreceptor currents (MRCs) in ASH neurons. The force required to activate ASH is two orders of magnitude larger than that required for activation of the PLM gentle touch receptor neurons (O’Hagan et al., 2005). MRCs in ASH are both Na+-dependent and inhibited by amiloride, properties of DEG/ENaC channels. Indeed, the major component of MRCs in ASH nociceptors was dependent on deg-1, a gene that encodes a DEG/ENaC channel

subunit. Deleting DEG-1, uncovered a second, minor current that was deg-1-independent and had the same activation kinetics as the total current, but a distinct current-voltage relationship indicating that it is not carried www.selleckchem.com/products/OSI-906.html by a DEG/ENaC channel. This minor current was also independent of osm-9 and ocr-2, since MRCs were similar in deg-1 single mutants and osm-9ocr-2;deg-1 triple mutants. Both TRPV proteins were also dispensable for the major component since MRCs were essentially wild-type in osm-9 and ocr-2 single mutants as well as in osm-9ocr-2 double mutants. Additionally, mechanoreceptor potentials (MRPs) evoked by saturating stimuli were likewise unaffected by the loss of OSM-9 and OCR-2. These data suggest that TRPV channels have a critical role PAK6 in later

steps of sensory perception: encoding and transmission of sensory information, but not in detection. We used a slit-worm preparation and in vivo whole-cell patch clamp recording (Goodman et al., 1998) to measure electrical responses to mechanical stimulation in ASH nociceptor neurons. To unambiguously identify ASH in both wild-type and mutant animals, we expressed green fluorescent protein (GFP) under the control of an ASH-selective promoter (Experimental Procedures). Using this label also allowed us to determine that the sensory ending of ASH remained intact after the cell body was exposed for patch-clamp recording. These sensory endings innervate structures next to the mouth of the animal called amphids. We applied mechanical stimuli to ASH by compressing the entire “nose” of the animal (Figure 1A), an area defined as the buccal cavity and surrounding sensory structures. We found that compressing the nose of immobilized C. elegans nematodes activates an inward MRC in wild-type ASH neurons. This current rises rapidly and decays during force application ( Figure 1).

We next examined the effect of the Syt1 KD on the electrophysiolo

We next examined the effect of the Syt1 KD on the electrophysiological activities of neurons in awake, freely moving mice. Hippocampal theta oscillations are critical for hippocampus-dependent learning and memory (Buzsáki, 2002 and Goutagny et al., 2009). Theta oscillations are generated by a combination of synchronized excitatory inputs to CA1 and local neuronal activity, especially the activity of local interneurons that may produce feedback inhibition onto medial septum neurons for pacemaking Apoptosis inhibitor of oscillations (Buzsáki,

2002). Recent studies indicated that theta pacemaking may originate in the CA1 region, providing further support for the hypothesis that CA1 region local neurons are critical for theta oscillation (Goutagny et al., 2009). The AAV infection in our experiments included all CA1 pyramidal cells and interneurons as well as most DG neurons (which influence CA1 region activity via direct innervation of CA3 region neurons), providing us with a system to evaluate the impact of manipulations of synaptic transmission on local oscillations. We recorded local field potentials in CA1 in awake, freely moving mice and found that TetTox significantly

reduced the power of theta oscillations, consistent with a critical role of the infected neurons in the generation of these oscillations (Figures 3A–3C). In contrast to TetTox, however, the Syt1 KD did not reduce the overall power of the oscillations but produced a shift in the peak frequency of click here the theta oscillations toward slightly higher frequencies (Figures 3A–3C). These results suggest that Endonuclease the residual synaptic release induced by spike bursts after the Syt1 KD is sufficient for the generation of theta oscillations. It appears likely that the change in synaptic transmission induced by the Syt1 KD altered the interaction between the hippocampus and septum (Buzsáki, 2002), thereby shifting the peak frequencies. Although it is premature to provide a mechanistic account for this observation, because the exact location

and mechanism of pacemaking of theta oscillations are not yet clear, these results further demonstrate that the Syt1 KD does not simply block the communication between neurons, but rather institutes a filter that permits selective propagation of high-frequency information. It needs to be noted that a small group of interneurons in the hippocampus express Syt2 instead of Syt1 (Kerr et al., 2008) and would not be affected by the Syt1 KD and may contribute to the generation of theta oscillations. To examine whether synaptic transmission mediated by isolated spikes and/or precise timing of synaptic transmission triggered by spike bursts in the hippocampus is essential for learning and memory, we tested the effect of the hippocampal Syt1 KD on contextual and cued fear conditioning.