Chelsea interested in Fedor Chalov in January if UEFA transfer ban is overturned
by Lyall ThomasChelsea have been monitoring CSKA Moscow striker Fedor Chalov in case they can do January transfer business.
Chelsea owner Roman Abramovich is understood to be a fan of his fellow Russian and the Blues are said to be interested if their transfer ban is overturned next month.
Chelsea expect to find out in mid-December whether their appeal against UEFA's punishment is successful, and, if it is, they are prepared to enter the transfer market in January.
Crystal Palace also remain interested in Chalov after having a number of bids rejected for the 21-year-old in the summer and are prepared to pay as much as £25m for a new striker in January.
Their final summer offer came on Deadline Day to the sum of £23m and it was knocked back - but a source has told Sky Sports News that CSKA are preparing for his exit during their winter break by searching for a replacement.
Chalov - a Russia international with two caps - came through the youth ranks at CSKA and has scored 32 Russian top-flight goals for them, including five in 16 appearances this term.
Palace are also understood to be keen to sign two new full-backs in January and want to sign players under the age of 23.


...The one with a lot of Quotes...
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Welcome to the jQuery S3 browser example. You'll need to edit this file adding your AWS settings (accesskeyId, secretAccessKey, region) and your bucket name and optional filter prefix (the element data attributes, data-bucket and data-prefix).


Located on the SW corner of Evia, this fishing village is a useful stop on your way north.
There are Port Police stationed here.
Moor where there is space on the western side of the harbour. Many of the original buoys are now missing or used by local boats so when dropping the anchor to moor bows or stern to, use a long scope to avoid the old ground tackle. Good shelter from the northerlies.
Last updated August 2009.


| Assigns a variable for use into a TYPE object structure. |
| variable = any legal variable |
Command Description:
| If you haven't read up on the TYPE
command, you might want to do so before continuing.
When you define a custom Type, you need to assign some variables to track within in. Using the Field command within the Type .. End Type commands, you set a variable that can be used for EACH object created with the NEW command. |
Example:
| ; Define the CHAIR Type Type CHAIR Field X Field Y Field HEIGHT End Type ; Create 100 new chairs using FOR ... NEXT using the collection name of ROOM For tempx = 1 to 10 ; Move them all over 1 (like the description example from TYPE command) For room.chair = Each chair |


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- Projects
- Downloads
- Documents
- Forum
- Contact
- About me
|
|
| Platform: |
Windows |
| License: |
Freeware |
| Release: |
1.02 |
| Last update: |
4 September 2003 |
| Description: |
An implementation of the octree algorithm used
to reduce the number of colors, finding the optimal palette of
the image |
Introduction |
|
This article shows an implementation of the octree
algorithm used to reduce the number of colors, finding the
optimal palette of the image. The applications of the
algorithm range from optimized drawing routines, graphic
tools, file format conversion utilities.
For this purpose, I will use the CQuantizer
class, developed in 1996-97 by Jeff Prosise, and described
with 2 articles in the MSDN. The original code has been
written to display images on 256-color display devices in the
end of the 16-bit era; but nowadays some functions can be
replaced, so I changed the memory allocation functions and
removed the need of a device context, to make the class a bit
more portable. |
What's new |
|
In this update there are only 2 minor changes. The first is
a small bugfix in CQuantizer::ProcessImage, which
causes strange results in small images (let's say icons) with
8 bit per pixel or less, when you try to reduce the number of
colors down to 16 or less.
The second change is an improvement to avoid a limit of the
octree algorithm: the reduction comes on the leafs of the
tree, each of them hold 8 colors, and for less than 16 colors
there are only 2 leafs; so the reduction for a really small
number of colors needs a different process. This has been
implemented in CQuantizer::SetColorTable , with
the help of some additional information gathered by
CQuantizer::GetPaletteColors .
| |
original true-color image |
reduction to 16 colors |
|
reduction to 8 colors |
reduction to 4 colors |
|
|
The images above show some good results, achievable when
the cromatic contents are not very complex, but don't pretend
the same quality for all the kinds of images.
|
Class Members & Operations |
CQuantizer (UINT
nMaxColors, UINT nColorBits) |
Construction and
initialization.
nMaxColors = maximum
number of colors permitted in the
palette.
nColorBits = number of
significant bits in each 8-bit color component. For
example nColorBits = 6 tells the algorithm to ignore the
lower two bits of each color component. A setting of 5
or 6 generally produces a palette that is pleasing to
the eye while keeping the octree’s memory requirements
to a reasonable minimum. nColorBits = 8 is required for
reduction to 16 colors or less, when the precision is
very important. |
ProcessImage (HANDLE
hImage) |
Processes the image to find
the optimal palette.
hImage = DIB image
handle. |
SetColorTable (RGBQUAD*
prgb) |
Transfers the optimized
palette to a RGBQUAD structure. The size of the
structure must be at least
nMaxColors . |
GetColorCount () |
Returns the number of colors found in
the optimized
palette | |
Example |
|
This example shows an application of
CQuantizer with the CxImage
class: CxImage image("test.bmp",CXIMAGE_FORMAT_BMP);
CQuantizer q(16,8);
q.ProcessImage(image.GetDIB());
RGBQUAD* ppal=(RGBQUAD*)malloc(16*sizeof(RGBQUAD));
q.SetColorTable(ppal);
image.DecreaseBpp(4,ppal);
free(ppal); |
|
|
|
|
|
|
| 2003 - 2004 © Davide
Pizzolato - www.xdp.it |
|
|
|


When rhesus monkeys ( Macaca mulatta) are used to test malaria vaccines, animals are often challenged by the intravenous injection of sporozoites. However, natural exposure to malaria comes via mosquito bite, and antibodies can neutralize sporozoites as they traverse the skin. Thus, intravenous injection may not fairly assess humoral immunity from anti-sporozoite malaria vaccines. To better assess malaria vaccines in rhesus, a method to challenge large numbers of monkeys by mosquito bite was developed.
Several species and strains of mosquitoes were tested for their ability to produce Plasmodium knowlesi sporozoites. Donor monkey parasitaemia effects on oocyst and sporozoite numbers and mosquito mortality were documented. Methylparaben added to mosquito feed was tested to improve mosquito survival. To determine the number of bites needed to infect a monkey, animals were exposed to various numbers of P. knowlesi-infected mosquitoes. Finally, P. knowlesi-infected mosquitoes were used to challenge 17 monkeys in a malaria vaccine trial, and the effect of number of infectious bites on monkey parasitaemia was documented.
Anopheles dirus, Anopheles crascens, and Anopheles dirus X (a cross between the two species) produced large numbers of P. knowlesi sporozoites. Mosquito survival to day 14, when sporozoites fill the salivary glands, averaged only 32% when donor monkeys had a parasitaemia above 2%. However, when donor monkey parasitaemia was below 2%, mosquitoes survived twice as well and contained ample sporozoites in their salivary glands. Adding methylparaben to sugar solutions did not improve survival of infected mosquitoes. Plasmodium knowlesi was very infectious, with all monkeys developing blood stage infections if one or more infected mosquitoes successfully fed. There was also a dose-response, with monkeys that received higher numbers of infected mosquito bites developing malaria sooner.
Anopheles dirus, An. crascens and a cross between these two species all were excellent vectors for P. knowlesi. High donor monkey parasitaemia was associated with poor mosquito survival.  It is possible to efficiently challenge large groups of monkeys by mosquito bite, which will be useful for P. knowlesi vaccine studies .
In 1931, Plasmodium knowlesi was identified as an infection of monkeys [ 1], and the following year it was experimentally transmitted to humans [ 2]. The first naturally occurring case of P. knowlesi in humans was reported in 1965 [ 3]. In 2004, it was discovered that P. knowlesi frequently infects humans in Southeast Asia [ 4], a finding which required PCR to distinguish P. knowlesi from Plasmodium malariae.
Plasmodium knowlesi infections in rhesus monkeys have been used as a model system to test malaria vaccines [ 5- 24]. The advantages of this model system are that the immune systems of rhesus monkeys and humans are similar, and that P. knowlesi sporozoites are extremely infectious. Often, monkeys are challenged with malaria by the intravenous (iv) inoculation of P. knowlesi sporozoites dissected from infected mosquitoes. Intravenous delivery of sporozoites to monkeys is quick, and 40 monkeys can be injected in two hours. Intravenous delivery also allows control of sporozoite doses. In vaccine trials at our laboratory challenge with 100 P. knowlesi sporozoites has been routine. With this dose, 56/56 control monkeys in 12 separate experiments (10 published [ 5- 9] and two unpublished) have all developed blood stage infections (estimated probability of infection 100%, 95% CI 93.6%, 100%). In one of these trials, 80% of vaccinated monkeys were protected against malaria, showing that this dose of sporozoites is not large enough to overwhelm the immune response. Because of the high infectivity, only several thousand sporozoites are needed to challenge the 30-40 monkeys in a vaccine trial. As P. knowlesi produces many thousands of sporozoites per mosquito, few mosquitoes are required to produce the sporozoites needed on the day of challenge.
However, the authors are now convinced that for testing of some malaria vaccines, challenge of monkeys should be by mosquito bite. Vanderberg et al.[ 25- 29] and others [ 30- 34] have shown how malaria sporozoites are deposited into the skin, blood, and other tissues during probing. They have also shown that antibodies can trap sporozoites in the skin, preventing them from reaching the liver. Intravenous injection of sporozoites bypasses the barrier of the skin, and might underestimate the effect of vaccines based on antibodies that neutralize sporozoites [ 28]. Not all malaria vaccines produce antibodies to sporozoites. Some vaccines, such as DNA plasmid vaccines, produce few or no antibodies in monkeys or humans, and seem to induce only T cell immune responses. Other vaccines contain antigens expressed in malaria blood or liver stages but not in the sporozoite. Intravenous challenge may be a reasonable method for testing such vaccines. However, many malaria sporozoites inoculated by mosquito bite end up in the skin or draining lymph nodes and not in the blood stream [ 31, 35]. It is theoretically possible that the immune responses to these lymphatic sporozoites might increase or decrease vaccine responses against malaria antigens of any parasite stage. Plasmodium knowlesi liver stages last only 4.5 days [ 1], so it is unlikely that vaccine responses would be altered by lymphatic sporozoites in time to affect intra-hepatic immune responses. In contrast, P. knowlesi blood stages can persist for weeks or months, and immune responses to lymphatic sporozoites could conceivably alter blood stage immunity and have consequences for vaccine efficacy.
The goal of these studies was to develop a P. knowlesi challenge model for rhesus monkeys using the bite of infected mosquitoes. While monkeys have been infected with P. knowlesi by mosquito bite for biologic studies, mosquito bite challenge has never been used for testing P. knowlesi malaria vaccines. Theoretically, the malaria exposure of monkeys in a vaccine trial should be adequate to show a statistically significant difference in infection between the control and vaccinated group. If the rate of infection is too low, very large group sizes are required to detect differences. If malaria exposure is too high, it may overwhelm the vaccine or not reflect actual transmission in endemic settings. In practice, with the small group sizes of five to eight monkeys in malaria studies, the goal is to use a malaria exposure which will infect all control monkeys with high probability.
As mentioned above, there is high confidence that 100 P. knowlesi sporozoites given iv will infect a rhesus monkey. It is estimated that 1-2.5 sporozoites per second are injected from the mosquito during secretion of saliva while probing the skin [ 27], which may be a physical limitation based on sporozoite diameter and mosquito anatomy. Thus, in the minutes required for one mosquito to probe the skin, several hundred sporozoites might leave the mosquito, although not all of these would reach the bloodstream. Thus, one mosquito bite should be adequate to reliably cause a blood stage infection with P. knowlesi.
In 1968, Chin et al.[ 36] exposed five human volunteers to P. knowlesi-infected Anopheles balabacencis balabacencis (= Anopheles dirus) mosquitoes. The volunteers received from one to nine infective bites. All five volunteers developed P. knowlesi infections in the blood. Thus it appeared possible that a single bite by a P. knowlesi-infected mosquito might be adequate to infect a monkey. The goal of the present study was determine the exposure to mosquitoes carrying P. knowlesi necessary to infect naive monkeys with high probability.
Anopheles dirus mosquitoes require mating by hand when grown in the laboratory, which is time-consuming. This led us to try other mosquito species and strains which are easier to rear. Anopheles crascens and a cross between An. dirus and An. crascens (termed Anopheles dirus X) were excellent hosts for P. knowlesi, and could be reared without forced mating. Unfortunately, P. knowlesi infections caused high mortality in mosquitoes. It was found that the parasitaemia level of the donor monkey affected the survival of infected mosquitoes and a low donor parasitaemia produced adequate numbers of sporozoites without great mosquito mortality. Methylparaben (MPB) added to sugar solutions [ 37] did not consistently reduce mortality. Finally, P. knowlesi-infected mosquitoes were used to challenge 17 monkeys in a vaccine study, and it was seen that increased numbers of bites led to more rapid onset of parasitaemia.
The experiments described in this paper were carried out at two facilities, the Walter Reed Army Institute of Research/Naval Medical Research Center, Silver Spring Maryland, USA (WRAIR/NMRC), or the Laboratory of Malaria Immunology and Vaccinology (LMIV) and the Laboratory of Malaria and Vector Research (LMVR), NIAID, NIH, Rockville, Maryland, USA. Adult Macaca mulatta bred in the US from Indian stock and maintained in facilities accredited by the Association for Assessment and Accreditation of Laboratory Animal Care were used in all studies. The experiments were conducted in compliance with the Animal Welfare Act and in accordance with the principles set forth in the “Guide for the Care and Use of Laboratory Animals,” Institute of Laboratory Animals Resources, National Research Council, National Academy Press, 1996. Experiments were approved by the Institutional Animal Care and Use Committee, WRAIR/NMRC or the NIAID Institutional Animal Care and Use Committee, NIH, depending on the location of the experiments. M. mulatta develops higher parasitaemias than do Macaca fascicularis and Macaca nemestrina, which are the natural hosts of P. knowlesi. All animals with malaria infections were closely monitored and treated with anti-malarial drugs, and adjunctive therapy was given as needed.
Plasmodium knowlesi H strain parasites were used in these experiments, and were derived from stocks at NIH. Oocysts were counted by removing the midgut of mosquitoes on day 7 after infection and counting under a dissecting microscope. Sporozoites in salivary glands were counted by removing the glands on day 14 and estimating the numbers of sporozoites using the following scale: 0 for none, 1 for 1-10, 2 for 11-100, 3 for 101-1,000, 4 for 1,001-10,000, 5 for >10,000.
After sporozoite challenge, from day 6 to day 30 blood was obtained by skin prick for thin film malaria slides. After Giemsa-staining, blood was examined under x1,000 magnification until an estimated 20,000 red cells on thin film were examined. Infected animals were treated with artesunate (5 mg/kg single dose) and chloroquine base (45 mg/kg total dose divided over five days). Animals were monitored for 30 days to ensure effectiveness of treatment in clearing malaria infections.
Anopheles dirus (= An. dirus A = An. balabascensis balabascensis ) were provided by the Malaria Research and Reference Reagent Resource Center . Anopheles crascens and An. dirus X (‘cross’) were provided by LMVR, NIH. Anopheles dirus X were produced at NIH by a mating of An. dirus males and An. crascens females. Anopheles stephensi and Anopheles gambiae were provided by WRAIR/NMRC.
All mosquitoes were infected with P. knowlesi malaria 4-6 days after adults emerged from pupae. Prior to infection, mosquitoes were fed 10% sucrose at WRAIR/NMRC, or 10% sucrose or 10% Karo brand syrup at NIH. Previously splenectomized monkeys were infected by iv injection of cryopreserved red blood cells infected with P. knowlesi. Splenectomy allows repeated infections with P. knowlesi without the animals developing immunity. In the authors’ experience, splenectomy does not affect gametocyte numbers or infectivity to mosquitoes. Feeding of mosquitoes on P. knowlesi-infected monkeys was carried out at 10 pm. 30-160 mosquitoes in a pint carton were starved for eight hours prior to the feed. Feeding was on a monkey anesthetized with ketamine and acepromazine. Hair was clipped on the chest or abdomen, and cups pressed against the skin under drapes for darkness. After feeding for 15-30 minutes, mosquitoes not engorged with blood were removed, and the remaining mosquitoes were maintained at 26°C and 85% humidity. Cotton pads soaked in sugar solution were changed daily. In some experiments, 10% sucrose was supplemented with methylparaben (MPB) beginning on the day after feeding. The MPB solution was made by adding 1gm of MPB (Sigma-Aldrich Corps. Louis, MO, USA) to 500 ml of a 10% glucose solution, filter sterilizing, and storing at 4°C.
Anopheles dirus X mosquitoes were used on days 14-16 after they had fed on a P. knowlesi-infected monkey. Mosquitoes were transferred to pint cups, starved of food and water overnight, and allowed to feed at 8 am on the chest or abdominal skin of monkeys. Monkeys were anesthetized with ketamine and acepromazine. After feeding, mosquitoes were dissected to determine the presence of P. knowlesi sporozoites in the salivary glands, and whether blood was visible in the midgut, as a measure of successful feeding. Monkeys were followed by blood film for 30 days to determine whether they became infected with malaria. In the preliminary studies, containers with three to 20 mosquitoes were exposed to each monkey for 15-30 minutes. In the vaccine challenge study, containers with five mosquitoes were exposed to each monkey for 15 min, in two groups of 8 and 9 monkeys.
Exact binomial confidence intervals were used to calculate the probability of infection after iv sporozoite injection. For Figure 1, non-parametric maximum likelihood estimators (NPMLEs) of survival were used (i.e., Kaplan-Meier for grouped right-censored data). Because there is a high correlation of the survival times of mosquitoes fed on the same monkey on the same day, standard survival models could not be used. For survival analyses on mosquitoes, Cox frailty models were used, with frailty effects for mosquitoes fed on the same day on the same donor monkey. In Table 1, Mann-Whitney U test tested for differences between continuous variables. In Table 2, the NPMLE for the proportion surviving to day 14 for each cup was calculated first. Then the mean of those proportions was taken within each mosquito species and feed group. The P-value is from the linear model with those proportions as response, controlling for mosquito species. A Cox frailty model with a random effect for mosquito group (a monkey donor on a specific day) was used to estimate the independent effects of species, experiment and donor parasitaemia on mosquito survival to day 15 after infection. A Cox regression analysis was used to calculate the effect of number of infected mosquito bites on time to first parasite in the blood. Calculations were done in R version 3.0.1 (using the survival and interval packages) or SAS v. 9.3.
Survival of heavily and lightly infected mosquitoes. Anopheles dirus mosquitoes were put into several pint containers and allowed to feed on a P. knowlesi infected monkey on consecutive nights, and survival to day 15 was monitored. For each group between 140 and 160 mosquitoes were fed. Figure 1 A shows the fraction of mosquitoes surviving from the first night feeds, either on an uninfected monkey or a P. knowlesi-infected monkey (parasitaemia of 0.2%). Figure 1 B shows survival of mosquitoes fed on the same two monkeys one day later, when the parasitaemia in the P. knowlesi-infected monkey was 2.6%. Because there was a strong day effect (logrank tests showed significant differences between control groups by day), we used a Cox frailty model using only parasitaemia level of the donor monkey, and with a separate frailty parameter for the four groups. There was a significant difference between the 2.6% group and the combined controls (p = 0.038), but no significant difference between the 2.6% group and the 0.2% group (p = 0.18).
Plasmodium knowlesi infections of mosquitoes fed on donor monkey on consecutive nights from Figure 1
| leftbottomMonkey donor parasitaemia | centerbottom0.2% | centerbottom2.6% | centerbottom |
| leftbottomMedian number of Oocysts (interquartile range) | centerbottom6.5 (2, 9.75) | centerbottom80(72.5, 100) | centerbottomp <0.0001 |
| leftSporozoites median grade (interquartile range) | center1.5 (1,2) | center3 (2.25,3.75) | centerp = 0.018 |
The results of dissections from the mosquitoes groups shown in Figure 1A and B. The oocyst counts are from 10 mosquitoes on day 7, and the sporozoite grading in the salivary glands from 10 mosquitoes on day 14. The mosquitoes fed on the high parasitaemia day produced more oocysts (P < 0.0001, Mann-Whitney U test), and sporozoites (P = 0.018, Mann-Whitney U test).
The effect on survival of adding methyparaben to mosquito feed
| leftbottomMosquito species | centerbottom | centerbottomdirus X | centerbottomdirus X | centerbottomcrascens | centerbottomdirus | centerbottomdirus X | centerbottomdirus | centerbottomdirus | centerbottomdirus X |
| leftbottomMosquito age at feed | centerbottom5 days | centerbottom8 days | centerbottom5 days | centerbottom5 days | centerbottom5 days | centerbottom5 days | centerbottom5 days | centerbottom5 days | centerbottom5 days |
| leftbottomMonkey donor parasitaemia | centerbottom12% | centerbottom12% | centerbottom1.30% | centerbottom5.50% | centerbottom5.50% | centerbottom5.50% | centerbottom0.30% | centerbottom0% (control) | centerbottom0% (control) |
| leftbottom% surviving fed sugar only (# replicate cups) | centerbottom53% (4) | centerbottom88% (4) | centerbottom87% (4) | centerbottom36% (1) | centerbottom41% (2) | centerbottom22% (1) | centerbottom64% (1) | centerbottom88% (1) | centerbottom24% (1) |
| leftbottom% surviving fed sugar + MPB (# replicate cups) | centerbottom91% (6) | centerbottom45% (2) | centerbottom81% (14) | centerbottom20% (1) | centerbottom29% (2) | centerbottom0% (1) | centerbottom41% (1) | centerbottom49% (1) | centerbottom2% (1) |
| left | centerp < 0.001 | centerp = 0.04 | centerp = 0.15 | 3centerp = .03 | centerNA | centerp = .18 | center |
Methylparaben (MPB) was added to the sugar solution used for feeding mosquitoes starting the day they were infected with P. knowlesi. Mosquitoes from the same batch were maintained on sugar solution without MPB. Experiments 1, 2 and 3 were on different dates, and have been subdivided by mosquito species and donor monkey. In some experiments, there were several replicate cups of mosquitoes for each feeding group. Sugar solutions on cages were changed daily. Percentage surviving is the mean from each cup to day 14. P-values were calculated as described in Methods section. For experiment 3d, there were only 2 cups and no statistical test could be done. MPB only improved survival in one of nine sub-experiments.
The first goal was to find a mosquito vector for P. knowlesi that was easy to maintain. Anopheles dirus is an excellent vector for P. knowlesi, but it requires hand mating in the laboratory, which limits its usefulness. Efforts were focused on mosquitoes that were easy to rear. In the first studies, an attempt was made to infect An. stephensi and An. gambiae, which had been reported to support P. knowlesi sporozoite development [ 38- 41] and which were readily available. Although these mosquitoes produced large numbers of oocysts, only an occasional sporozoite was found in the salivary glands, and work was not continued with these species. Three types of mosquitoes produced large numbers of P. knowlesi sporozoites: An. dirus, An. crascens, and a cross-mating of An. dirus males and An. crascens females termed An. dirus X (‘cross’). Both An. crascens and An. dirus X mosquitoes mate well in the laboratory and were more easily produced in large numbers than An. dirus.
Survival of P. knowlesi-infected mosquitoes of An. dirus, An. dirus X, and An. crascens were compared in five experiments at high and low donor parasitaemia. In monkeys, P. knowlesi parasitaemia increases 10-fold every day, so groups of mosquitoes fed on the same monkey on consecutive nights provided the low and high parasite groups.  Figure 1 and Table 1 show representative data from one of the experiments.
Mosquitoes feeding on donor monkeys with a high parasitaemia had large numbers of oocysts in the midgut dissections on day 7, high levels of sporozoites on gland dissections on day 14, but poor survival. Mosquitoes fed on the same donor monkeys a day earlier when the parasitaemia was lower, had smaller numbers of oocysts and sporozoites, and better survival. This was true for An. dirus, An. dirus X, and An. crascens mosquitoes. Overall, 16 groups of mosquitoes were fed on monkeys with a parasitaemia greater than 2%, and the median of the day 14 survival was 32% (interquartile range [IQR]: 23%, 38%). All three types of mosquitoes produced large numbers of P. knowlesi sporozoites (see Additional file 1 for complete data). Survival data from the five experiments were analysed using a Cox Frailty model. Higher donor parasitaemia was significantly associated with lower mosquito survival (p-value <0.001) after correcting for mosquito species effects and experiment effects.
Methylparaben (MPB) is an antibacterial and antifungal agent which can improve the survival of malaria-infected mosquitoes when maintenance sugar solutions are changed infrequently [ 37]. The addition of MPB to the sugar solution was tested in our laboratories where sugar pads are changed daily. Three experiments were done adding MPB at 2 gm/L to the sugar solutions of some mosquitoes while others received standard sugar solution. Table 2 shows the effect of MPB on the percentage of mosquitoes surviving to day 14 after P. knowlesi infection. In Experiment 1a using mosquitoes aged 5 days at feed, MBP enhanced survival. In Experiment 1b using mosquitoes aged 8 days at feed there was a significant worsening of survival (p = 0.04). In Experiment 2, there was no significant difference in survival. Experiment 3 had six subgroups of mosquitoes fed on monkeys with 5.5%, 0.3% or no malaria infection. In all the subgroups of Experiment 3, MPB decreased the fraction of mosquitoes surviving until day 14, but the difference was significant only in the mosquitoes fed on the donor monkey with 5.5% parasitaemia. Overall, the effects of MPB on survival were inconsistent.
Over several years, 49 monkeys were exposed to varying numbers of mosquitoes (3 to 20) for 15 to 30 min. Immediately after, mosquitoes were dissected to determine the numbers of sporozoites in the salivary glands and the presence of ingested blood as a mark of successful feeding. Monkeys were followed for 30 days to determine if parasitaemia developed. The results of mosquito dissections and monkey infections are summarized in Table 3 (see Additional file 2 for complete data). Exposures were placed into Categories A, B, C or D of decreasing intensity. Category A exposures were the most intense, with two or more dissected mosquitoes having both P. knowlesi sporozoites and ingested blood as a sign they had probed and injected sporozoites. Nine exposures were in Category A, and all led to P. knowlesi infections in the monkeys. Category B exposures had only one mosquito with both sporozoites and ingested blood. Eight exposures were in Category B and all eight led to monkey infections. Category C exposures were those where one or more mosquitoes carried P. knowlesi sporozoites, even though it had not ingested blood. Ten exposures were in Category C, and 4 of these led to infected monkeys. Finally, Category D exposures were those where upon dissection no mosquitoes were found to carry P. knowlesi sporozoites. 22 exposures were in Category D, and 1 of these monkeys developed a P. knowlesi infection.
Summary of exposure to P. knowlesi -infected mosquitoes vs. monkey infection
| centerbottomA | centerbottom≥ 2 | centerbottom0 to 10 | centerbottom9 | centerbottom100 |
| centerbottomB | centerbottom1 | centerbottom0 to 8 | centerbottom8 | centerbottom100 |
| centerbottomC | centerbottom0 | centerbottom≥ 1 | centerbottom10 | centerbottom40 |
| centerD | center0 | center0 | center22 | center4 |
From 3-20 mosquitoes infected with P. knowlesi were exposed to a monkey for 15-30 minutes on 49 occasions. Mosquitoes were dissected to grade the sporozoites in the salivary glands, and identify ingested blood in the mosquito midgut. Monkeys were followed for 30 days to see if they developed parasites in the blood. Category A exposures had two or more mosquitoes containing both sporozoites and blood. Category B exposures had only one mosquito with both sporozoites and blood. Category C exposures had some mosquitoes with sporozoites but none of these had ingested blood. Category D exposures had no mosquitoes with any sporozoites in the salivary glands, nor any mosquitoes with ingested blood.
Category B exposures show that even a single P. knowlesi-infected mosquito feeding is enough to transmit malaria to a non-immune monkey. Of the eight mosquitoes positive for both sporozoites and ingested blood in Category B, five had only grade 2 sporozoites (11-100) in the salivary gland dissections (the remaining three mosquitoes had P. knowlesi sporozoites but were not quantitated). The results from Category C exposures were even more surprising. Mosquitoes inject sporozoites while they are probing the skin looking for a blood vessel. Monkey infections from Category C exposures occurred without mosquitoes having ingested blood, so presumably the sporozoites which initiated these infections were transmitted to the monkey during probing which did not result in blood feeding. That 40% of these exposures led to monkey infections shows that successful feeding is not required for transmission of P. knowlesi. In theory, Category D exposures should not have resulted in any monkey infections, but one of 22 monkeys became infected. It is probable that the mosquito dissections missed a very small number of sporozoites or that all sporozoites were injected into the monkey during feeding. Overall, we conclude that P. knowlesi can be transmitted to monkeys extremely efficiently by P. knowlesi-infected mosquitoes. Feeding by a single infected mosquito carrying only modest numbers of sporozoites consistently transmitted malaria to monkeys.
To produce P. knowlesi sporozoites, mosquitoes were used 4-6 days after they emerged from pupae to adult. On the day of feeding, it was usual to have 95% of these young mosquitoes take a blood meal. Unfed mosquitoes were then removed and the mosquitoes kept for 14 days while oocysts and then sporozoites developed. Mosquitoes were used to infect monkeys by bite on day 14-16. Blood feeding rates for these older P. knowlesi-infected mosquitoes was near 50% but ranged from 10 to 90%.
Based on experience outlined in Table 3, a mosquito bite challenge was planned to test a monkey malaria vaccine based on the P. knowlesi sporozoite circumsporozoite protein. Details of the study are being published elsewhere. In this paper, technical aspects of the malaria challenge by exposure to P. knowlesi-infected mosquitoes will be discussed.
Seventeen monkeys were challenged with malaria by mosquito exposure. Six monkeys had received a control vaccine and 11 had received malaria vaccine. It was decided to aim for an exposure that would result in blood ingestion by at least two mosquitoes carrying P. knowlesi sporozoites. Each monkey was exposed to five An. dirus mosquitoes for 15 minutes as described in the methods section. Results are shown in Table 4.
Results of a mosquito bite challenge in 17 rhesus monkeys
| centerbottom1 | centerbottomControl | centerbottom2 | centerbottom4,4 | centerbottom9 |
| centerbottom2 | centerbottomControl | centerbottom3 | centerbottom4,4,4 | centerbottom8 |
| centerbottom3 | centerbottomControl | centerbottom3 | centerbottom4,4,4 | centerbottom8 |
| centerbottom4 | centerbottomControl | centerbottom4 | centerbottom4,4,4,4 | centerbottom8 |
| centerbottom5 | centerbottomControl | centerbottom4 | centerbottom4,4,4,4 | centerbottom7 |
| centerbottom6 | centerbottomControl | centerbottom4 | centerbottom2,4,4,4 | centerbottom9 |
| centerbottom7 | centerbottomVaccine | centerbottom2 | centerbottom4,4 | centerbottom7 |
| centerbottom8 | centerbottomVaccine | centerbottom3 | centerbottom4,4,4 | centerbottom7 |
| centerbottom9 | centerbottomVaccine | centerbottom3 | centerbottom4,4,4 | centerbottom9 |
| centerbottom10 | centerbottomVaccine | centerbottom3 | centerbottom2,4,4 | centerbottom8 |
| centerbottom11 | centerbottomVaccine | centerbottom4 | centerbottom2,3,4,4 | centerbottom8 |
| centerbottom12 | centerbottomVaccine | centerbottom4 | centerbottom4,4,4,4 | centerbottom9 |
| centerbottom13 | centerbottomVaccine | centerbottom4 | centerbottom4,4,4,4 | centerbottom7 |
| centerbottom14 | centerbottomVaccine | centerbottom4 | centerbottom3,4,4,4 | centerbottom7 |
| centerbottom15 | centerbottomVaccine | centerbottom5 | centerbottom4,4,4,4,4 | centerbottom9 |
| centerbottom16 | centerbottomVaccine | centerbottom5 | centerbottom2,4,4,4,4 | centerbottom7 |
| center17 | centerVaccine | center5 | center4,4,4,4,4 | center7 |
17 rhesus monkeys were exposed to five P. knowlesi infected mosquitoes for 15 minutes, in two groups of 8 and 9 monkeys each. The six control monkeys and 11 monkeys receiving malaria vaccine were challenged in random order, but are shown by group for ease of analysis. Mosquitoes were dissected to determine sporozoite grade in the salivary glands and the presence of ingested blood. All 17 monkeys developed parasites in the blood, and the first day parasites were detected is recorded.
The 17 monkeys were challenged in random order but are listed in Table 4 by vaccine group for clarity. After feeding, when the mosquitoes were dissected, from 2 to 5 carried both sporozoites and ingested blood in containers from each of the 17 monkeys. Of the 85 mosquitoes in the challenge, 62 were found to have ingested blood for a bite rate of 73%. All monkeys developed P. knowlesi malaria parasites in the blood on day 7 to 9 after exposure. There was no significant difference in time to first parasitaemia in control versus vaccinated monkeys (Logrank test, p = 0.46).
When sporozoites are injected by mosquito, they travel quickly to the liver, and begin to develop inside hepatocytes. Hepatocyte development averages 4.5 days for P. knowlesi[ 1], after which thousands of merozoites from each hepatocyte enter the blood and infect red blood cells. In theory, monkeys with few infected hepatocytes will have lower numbers of merozoites entering the blood than monkeys with large numbers of infected hepatocytes. Since a constant number of red blood cells on each slide is examined, the injection of larger numbers of sporozoites would be expected to lead to earlier detection of parasites.
The number of infected mosquito bites correlated with the time when parasites were first detected in the blood. Of the 49 infections of non-immune monkeys, 13 had complete data on both number of infected mosquito bites and day of first parasitaemia. Combining these 13 with the 17 monkeys from vaccine challenge, and using Cox regression, effects of experiment and number of mosquito bites on time to first detection were examined. As there was no significant effect of experiment, a simpler Cox model was used with only number of mosquito bites as a predictor. Figure 2 shows a graph of these data. Each additional bite increased the hazard by a factor of 1.41 (95% CI: 1.08, 1.82). As it was possible that the monkey receiving 10 mosquito bites was driving the results, the analysis was repeated without this data point but the results were similar (HR = 1.28, 95% CI: 0.95, 1.73). The authors conclude that increasing numbers of infected mosquito bites lead to earlier detection of P. knowlesi in the blood.
Effect of number of infected mosquitoes feeding on day parasites detected in blood. Thirty monkeys were infected with P. knowlesi by the bite of from 1 to 10 mosquitoes which had sporozoites in the salivary glands and had ingested blood. The day on which the first P. knowlesi parasites were found in the blood is plotted against the number of infectious bites. Increasing numbers of bites lead to earlier detection of parasites in the blood. Cox regression analysis shows the number of infected mosquito bites increased the hazard of parasites appearing in the blood (p = 0.01).
The aim of these studies was to learn how to challenge monkeys with the bite of P. knowlesi-infected mosquitoes for vaccine studies. However, the first problem was to produce enough P. knowlesi-infected mosquitoes that survived until sporozoites appeared in the salivary glands. The high death rate of P. knowlesi-infected mosquitoes was something of a surprise. In the 1960’s and 1970’s, An. dirus sensu lato produced large numbers of P. knowlesi sporozoites without excessive losses of infected mosquitoes (Robert Gwadz, personal communication). These mosquitoes often carried several hundred oocysts, and dissections of salivary glands yielded up to 250,000 P. knowlesi sporozoites per mosquito. Why are the current death rates of the infected mosquitoes so high? It is possible that the current P. knowlesi and mosquito strains available are different from those used 40 years ago. However, this history gave hope that we could produce the numbers of P. knowlesi-infected mosquitoes required for vaccine studies.
Mosquitoes fed on monkeys with a high parasitaemia developed large numbers of oocysts, but had high death rates during the second week, so that by 14 days after the feed there were sometimes only 10% of mosquitoes surviving. Control groups which were fed on uninfected monkeys or on monkeys with a lower parasitaemia typically had survival of greater than 70%. This difference in mortality between heavily and lightly infected mosquitoes happened in all the species and strains of mosquitoes we tested. It also occurred in both insectaries used for these studies, the one at WRAIR/NMRC in Silver Spring MD, and the other at NIH in Rockville MD. It is not understood what is causing the death of heavily infected mosquitoes. One possibility is that there is something toxic in the blood of monkeys that have high levels of P. knowlesi infection, such as a cytokine [ 42], which might be detrimental to mosquitoes. However, if a toxic substance was ingested, mosquito mortality might be expected to be highest soon after they fed on an infected monkey. However, the excess mosquito deaths happened after the first week of oocyst development, so it is not likely that a toxin from the monkeys is responsible for killing mosquitoes.
The large numbers of P. knowlesi oocysts may be contributing to mosquito death, but it seems less likely that the large numbers of sporozoites are harmful to the mosquitoes. Mortality in P. knowlesi-infected mosquitoes typically is not high during the first week, but increases 8-12 days after the feed on the infected monkey. During these days, oocysts are large in size but sporozoites have just begun to emerge into the haemolymph and enter the salivary glands. Mortality and stress from oocysts is supported by the results of the one experiment that included An. stephensi. Plasmodium knowlesi infection produced large numbers of oocysts in An. stephensi, but no sporozoites in the salivary glands. However, An. stephensi mosquitos fed on a control uninfected monkey had a survival rate to day 15 of 41.6% while mosquitos feeding on a monkey with 2.6% P. knowlesi infection had only a 15.4% survival rate (p < 0.001, Cox frailty model). Although this is data from a single experiment, it supports the theory that the excess mortality to is due to oocysts, not sporozoites.
This is not the first example of intense malaria infections increasing mortality in An. dirus mosquitoes. In 1986, Klein et al.[ 43] reported that when An. dirus were infected with Plasmodium cynomolgi, there was excess mortality in the infected groups. This mortality was only seen in mosquito groups with greater than 10 oocysts. Survival rates in all groups were similar during the first week, and only increased in the heavily infected mosquitoes beginning after the first 8 days of incubation. These results with P. cynomolgi infection exactly parallel the results with P. knowlesi infections of mosquitoes.
Other studies have looked at the role of malaria infection in mosquito survival. In a 2002 meta-analysis, Ferguson and Read [ 44] showed that although half of the studies reported no effect of Plasmodium on survival, the other half reported shorter lifespans in infected mosquitoes. The negative effects of Plasmodium on survival were more likely to appear in non-natural mosquito–parasite combinations, but the authors were unsure of the cause of the discrepant results.
Both An. dirus and An. crascens have been found infected with P. knowlesi in the wild [ 45, 46]. While they may not always be the primary vectors carrying P. knowlesi, it seems unlikely that the high mortality seen in this study is due to an artificial pairing of mosquito and parasite.
Two recent studies have looked at mortality in malaria-infected mosquitoes subjected to additional stress. Aboagye-Antwi et al.[ 47] caught An. gambiae in Mali and studied survival of mosquitoes with or without naturally occurring P. falciparum infections. They found that when water was provided, there was little difference in mortality between mosquitoes carrying malaria oocysts and uninfected mosquitoes. However, when water was withheld, the mosquitoes with oocysts died faster than the uninfected mosquitoes. Mosquitoes carrying sporozoites had the same survival as the uninfected mosquitoes.
In 2012, Vezilier et al.[ 48] investigated the role of egg-laying on the mortality of malaria-infected mosquitoes. Using a naturally occurring mosquito-parasite pair, they found no difference in survival between infected and uninfected groups when mosquitoes were not allowed to lay eggs. However, when egg-laying was allowed, infected mosquitoes laid fewer eggs but lived longer than the uninfected controls. They surmised that the parasite redirects the mosquitoes’energy away from egg laying into prolonging life. This highlights the complex parasite-host interactions which may affect mosquito survival.
Excess mortality in heavy P. knowlesi infections might be due to a stress on the mosquito midgut from the large number of P. knowlesi oocysts. This stress may peak around day 7 when oocysts reach their full size. Stress from oocysts may combine with other stresses that were not measured, such as bacterial or fungal infection, or sub-optimal culture conditions.
Data on the high infectivity of P. knowlesi-carrying mosquitoes is consistent with the early observations of Chin et al.[ 36], who found that a bite from a single infected mosquito was able to infect the one human volunteer tested. In our hands, a single exposure to a mosquito carrying P. knowlesi sporozoites caused a malaria infection in 8/8 attempts. Most of these infections by single bite were from mosquitoes with only 11-100 sporozoites in their salivary glands. This indicates that the P. knowlesi sporozoites from lightly infected mosquitoes are quite virulent. The data show that 4/10 monkeys exposed to P. knowlesi-infected mosquitoes developed malaria in the absence of a detected blood meal. This means that measurements of exposures to P. knowlesi malaria should not be limited to counting mosquitoes with both blood meals and sporozoites, as this may underestimate the true sporozoite inoculum.
Chin et al.[ 36] noted a dose response effect in their five human subjects, with more infected bites leading to earlier detection of parasites in the blood. The data in 30 monkeys confirm this finding. Our interpretation is that fewer infective bites lead to fewer sporozoites reaching the liver and fewer liver-stage schizonts. This translates into fewer merozoites released from the liver, and a longer time until parasites are first detected in the blood. Anything that reduces the number of sporozoites reaching the liver should have the same effect. Therefore, delay to first parasitaemia is a valuable way to evaluate partial efficacy of vaccines directed at P. knowlesi pre-erythrocytic stages.
A P. knowlesi mosquito bite challenge was used here in a monkey vaccine trial. 17 monkeys, six control and 11 vaccinated animals, were exposed to five P. knowlesi-infected mosquitoes for 15 minutes. The vaccine did not protect any of the monkeys, and all the control and vaccinated monkeys developed malaria parasites in their blood 7 to 9 days after exposure. Although the preliminary data suggested that a single bite from a P. knowlesi-infected mosquito was adequate exposure to infect controls, it was decided to aim for at least two infected bites for each animal. Two bites were chosen instead of one, as with data from only eight animals there was not great confidence that a single bite would always transmit malaria. This study was also influenced by data from murine malaria, where a single bite from an infected mosquito only produced malaria infection in 39% of mice [ 29]. By estimating that 90% of the batch of mosquitoes was carrying P. knowlesi sporozoites, and estimating that 50% of mosquitoes would succeed in taking a blood meal, it was calculated (using binomial probabilities) that exposing each monkey to five mosquitoes would deliver at least two infective bites to each animal with probability of about 75%. In retrospect, exposing each monkey to fewer infective mosquitoes (perhaps 3 or 4) would have provided at least one infective bite which would have been an adequate challenge. With more experience in vaccine challenges by mosquito bite using P. knowlesi, the authors hope to generate the data to answer this question.
Plasmodium knowlesi sporozoites in rhesus seem to be more infectious than Plasmodium falciparum sporozoites in humans. While the data show that one infective bite is probably adequate to infect a monkey, human studies have shown that volunteers exposed to two bites of P. falciparum-infected mosquitoes do not always become infected [ 49, 50]. This has led to the standard of five bites by P. falciparum-infected mosquitoes for laboratory-based malaria vaccine trials [ 51]. The reasons for this difference in virulence between P. knowlesi and P. falciparum are not understood. In the wild, most human infections by P falciparum and P. knowlesi are probably both caused by a single bite by a Plasmodium-carrying mosquito.
Adding methylparaben to the sugar water of infected mosquitoes did not improve survival. The original paper describing methylparaben [ 37] in mosquitoes carrying Plasmodia indicated that survival benefits were not evident when sugar pads were changed daily. As sugar pads were changed every day in our insectaries, the failure to see improvement was not surprising.
 Lower donor parasitaemias allow better mosquito survival and adequate sporozoite production.  Based on these results, a plan has been formulated for future P. knowlesi challenges of malaria vaccines by mosquito bite: (1) Anopheles crascens or An. dirus X mosquitoes will be used; (2) mosquitoes will be fed on a donor monkey when parasitaemia is from 0.2 to 2.0%; and (3) the goal of exposure will be one mosquito having both P. knowlesi sporozoites in the salivary glands of grade 2 (11-100) and ingested blood in the midgut. To achieve this single infectious bite, challenge will start with one exposure to mosquitoes, with a second exposure if necessary. For the first exposure, the number of infective P. knowlesi mosquitoes exposed to each monkey will be calculated from dissection of 10 mosquitoes to estimate the percentage having at least grade 2 (11-100) sporozoites in the salivary glands, and assuming a 50% bite rate. (For example, if 100% of mosquitoes are carrying P. knowlesi sporozoites, each monkey would be exposed to two mosquitoes.) All monkeys will receive this exposure for 15-30 minutes to allow as many mosquitoes to take a blood meal as possible. After exposure, all mosquitoes will be dissected to determine the number of mosquitoes carrying P. knowlesi sporozoites that ingested blood from each monkey and the actual bite rate will be calculated. If any animals have not received one infective bite in the first exposure, these monkeys will be exposed to P. knowlesi-infected mosquitoes from the same batch a second time. The second exposure may be on the same day as the first exposure or the day following, the timing depending on the ability of the monkeys to tolerate anesthesia. The number of mosquitoes used for the second exposure will be calculated using the rate of sporozoite infection and the actual bite rate from the first exposure.
MPB: Methylparaben; WRAIR/NMRC: Walter Reed Army Institute of Research/Naval Medical Research Center; LMIV: Laboratory of Malaria Immunology and Vaccinology; LMVR: Laboratory of Malaria and Vector Research.
The authors declare that they have no competing interests.
JM, WW, DF, and LL fed mosquitoes on monkeys. JC, CS, MD, TS, OM, SO-G, KLZ and JH counted parasites in mosquitoes or on blood films. MF and GJ did the statistical analysis. RG, TR, EV, JR and PD provided advice and guidance. All authors read and approved the final manuscript.
Experiments 1 to 5 of mosquito survival after P. knowlesi infection. Description of data: This spreadsheet provides the mosquito species, donor monkey parasitaemia, total number of mosquitoes alive, and the oocyst and sporozoite dissection results for five separate experiments.
Click here for file
Monkey infections after exposures to P. knowlesi infected mosquitoes. Description of data: This spreadsheet provides the infection results of 49 monkey exposures to P. knowlesi infected mosquitoes, as well as the data from the mosquito dissections.
Click here for file
We thank Paul Howell, Kevin Lee and Andre Laughinghouse for their help producing mosquitoes for these experiments. Financial support was provided by NIH grant #1R01AI068761-01A2, PATH/MVI grant #COL-CRADA 7872, Malaria Research and Reference Reagent Resource Center grant HHSN272201000027C, the Intramural Research Program of NIAID, and funds allocated to the Naval Medical Research Center by the U.S. Army Medical Research Materiel Command (work unit 6000.RAD1.F.A0309). The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. Title 17 U.S.C. §105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ The experiments reported herein were conducted in compliance with the Animal Welfare Act and in accordance with the principles set forth in the “Guide for the Care and Use of Laboratory Animals,” Institute of Laboratory Animals Resources, National Research Council, National Academy Press, 1996.


|
tpl2dox demo
catage example
catage.tpl
|
Variables | |
| sdreport_number | avg_F |
| matrix | C (1, nyrs, 1, nages) |
| init_bounded_dev_vector | effort_devs (1, nyrs,-5., 5., 3) |
| matrix | F (1, nyrs, 1, nages) |
| objective_function_value | f |
| number | initsum |
| vector | log_initpop (1, nyrs+nages-1) |
| init_number | log_popscale (1) |
| init_number | log_q (1) |
| init_bounded_dev_vector | log_relpop (1, nyrs+nages-1,-15., 15., 2) |
| vector | log_sel (1, nages) |
| init_bounded_dev_vector | log_sel_coff (1, nages-1,-15., 15., 2) |
| matrix | N (1, nyrs, 1, nages) |
| likeprof_number | pred_B |
| sdreport_vector | predicted_N (2, nages) |
| sdreport_vector | ratio_N (2, nages) |
| number | recsum |
| matrix | S (1, nyrs, 1, nages) |
| matrix | Z (1, nyrs, 1, nages) |
| sdreport_number avg_F |
Definition at line 285 of file catage.tpl.
Referenced by evaluate_the_objective_function(), and get_catch_at_age().
| init_bounded_dev_vector effort_devs(1, nyrs,-5., 5., 3) |
Referenced by evaluate_the_objective_function(), and get_mortality_and_survivial_rates().
Referenced by evaluate_the_objective_function(), get_catch_at_age(), and get_mortality_and_survivial_rates().
Definition at line 282 of file catage.tpl.
| number initsum |
Definition at line 284 of file catage.tpl.
Referenced by get_numbers_at_age().
| init_number log_popscale(1) |
Referenced by get_numbers_at_age().
| init_number log_q(1) |
Referenced by get_mortality_and_survivial_rates().
| init_bounded_dev_vector log_relpop(1, nyrs+nages-1,-15., 15., 2) |
Referenced by evaluate_the_objective_function(), and get_numbers_at_age().
Referenced by get_mortality_and_survivial_rates().
| init_bounded_dev_vector log_sel_coff(1, nages-1,-15., 15., 2) |
Referenced by get_mortality_and_survivial_rates().
Referenced by get_catch_at_age(), and get_numbers_at_age().
| likeprof_number pred_B |
Definition at line 290 of file catage.tpl.
| sdreport_vector predicted_N(2, nages) |
Referenced by get_numbers_at_age().
| sdreport_vector ratio_N(2, nages) |
Referenced by get_numbers_at_age().
| number recsum |
Definition at line 283 of file catage.tpl.
Referenced by get_catch_at_age(), get_mortality_and_survivial_rates(), and get_numbers_at_age().
Referenced by get_catch_at_age(), and get_mortality_and_survivial_rates().


§480-21 Court and venue. (a) Any criminal action or proceeding authorized by this chapter shall be brought in any appropriate court in the circuit in which the defendant resides, engages in business, or has an agent.
(b) Any civil action or proceeding authorized by this chapter may be brought in any appropriate court. [L 1961, c 190, §19; Supp, §205A-19; HRS §480-21; am L 1998, c 62, §1; am L 2011, c 66, §2]
Case Notes
Plaintiffs' chapter 480 claims which were derived through chapter 443B could not have been "properly litigated" in district court for the court lacked jurisdiction; thus, such claims were not precluded by doctrine of res judicata. 78 H. 213 (App.), 891 P.2d 300.


Each task on this page can be performed with only the techniques we've gone
over so far in class.
- Write a function that finds the largest value in a numeric array and outputs it to the console.
- Write a function that counts from 1 - 100 and echoes “BEEP” when it encounters multiples of 3 and 5.
- Write a function that finds the sum of all values when given an array of numbers
- Write a tip calculator that finds a 10%, 15%, and 20% tip for a given value. Write the values to an array.


Overview
Circles Overlap
Flare
Ego Node:
0
107
348
414
686
698
1684
1912
3437
3980
Circle 1:
Circle 2:


2 references to InputObject
Microsoft.PowerShell.Commands.Utility (2)
commands\utility\Join-String.cs (2)
111
if (
InputObject
!= null)
113
foreach (PSObject inputObject in
InputObject
)


24 November 1998
Disease Outbreak Reported
News Release from the Pan American Health Organization, Regional Office for the Americas, WHO, 23 November 1998
Controlling Diseases After Mitch Will Cost Money
Controlling communicable diseases in the countries devastated by Hurricane Mitch will require significant expenses to control disease-carrying mosquitoes and to ensure that water and food are not contaminated, according to Dr. Claude de Ville, Chief of the Pan American Health Organization's Emergency Preparedness and Disaster Relief Program.
Dr. de Ville, who just returned from Honduras and El Salvador, said, "One of our main concerns is control of communicable diseases. While we don't expect catastrophic outbreaks, that doesn't mean there will be no cases. Cholera, malaria, dengue and leptospirosis are all present in Central America. To control them, we must invest significant amounts in control of vectors, food, and water supplies."
Floods also increase risk of schistosomiasis, dengue, yellow fever, malaria, hantavirus, and other diseases, according to PAHO experts. PAHO's Assistant Director, Dr. Mirta Roses, cited the latest figures on communicable diseases that have been reported to PAHO by Ministries of Health, noting that many doctors and epidemiologists are out looking for cases to ensure that any outbreaks are rapidly controlled and the people treated. As a result of this increased attention, reporting is also increased, she said.
El Salvador has reported six confirmed cases of cholera including one death, all related to contaminated food sold by street vendors near the border of Guatemala.
Guatemala has reported 234 confirmed cholera cases with 17 deaths, along with seven cases of leptospirosis, six cases of dengue, and 70 cases of malaria. Cholera cases have appeared in different areas of the country, and all have been food-related. Five confirmed cases of leptospirosis have been reported, four in Guatemala City and two in Esquintla.
Nicaragua has reported 335 cholera cases and confirmed 301 in laboratories. The cases include 156 in Managua, 46 in Carazo, 25 in Masaya, 18 in Matagalpa, 16 in Chinandega, and 13 in Estelí, with the rest scattered in six other areas. Nicaragua has also reported 264 possible leptospirosis cases, of which 42 have been confirmed by laboratory, including 30 in Chinandega, 11 in Estelí, and one in Madriz. Seven people have died from leptospirosis, often transmitted by contact with water contaminated by rodent urine or feces.
Honduras has reported 14 cases of cholera, 4 cases of leptospirosis with three deaths, 1,080 cases of dengue, 15 confirmed cases of dengue hemorrhagic fever with four deaths, and 1,567 cases of malaria, including seven deaths.
Belize has reported a cholera outbreak in Saint Martin Village, with 11 suspected and five confirmed cases, including one death. The source of infection is thought to be contamined water from Roaring Creek, authorities said.
In all countries, health authorities have taken control measures to improve food safety and to guarantee the quality of water for human consumption, and have sent doctors and epidemiologists to areas where outbreaks have been reported to take control measures and educate the communities on preventive measures, Dr Roses said.
Emergency supplies are arriving and being widely distributed, using the PAHO-designed SUMA Humanitarian Supply Management system, Dr. de Ville said, "but we already see in the field many unusable supplies and expired medicines."
The real problem for Central America will be reconstruction and rehabilitation, Dr. de Ville said. "The big item for the health sector in Honduras, for example, is reconstruction of the water system, which we estimate will cost some $180 million out of an estimated $220 million in health reconstruction costs, and is a very important priority."
Noting that PAHO has mobilized some 60 experts to the countries hardest hit by the hurricane, in addition to the 150 already there, Dr. de Ville said, "We have a lot to learn from this disaster. Were we sufficiently prepared? Could we have done better? How can we emphasize disaster mitigation to ensure damages will not be so heavy next time?" He said an evaluation meeting will be held on Hurricanes Mitch and Georges February 9th to 12th.
PAHO, founded in 1902, provides technical collaboration in a broad range of fields including emergency preparedness and disaster relief. It works to improve health and living conditions in the countries of the Americas, and serves as the Regional Office for the Americas of the World Health Organization.


{% extends "layout.html" %} {% load staticfiles %} {% block content %}
The PASSIM application is a Django web application. Django is a high-level framework built on the Python programming language. The web application consists of the following parts:
The front-end is the user's browser. This is the system that the user interacts with first of all. The user sees HTML pages on the browser, and interacts with these pages via calls to 'Javascript' code. Whenever the user loads a HTML page, Javascript code is loaded too. Pressing buttons often results in the execution of a piece of Javascript code--something that takes place entirely on the user's browser. Some pieces of Javascript send POST or GET requests to the back-end server, resulting in dynamically updated web pages.
Data visualization on the site has been implemented using d3js, which provides svg pictures.
As for requirements - any up-to-date web browser should be able to handle this web application. The application has not been tested on all browsers, but it should at least work on Firefox and on Chrome.
The back-end application is the one that makes use of the Django-Python framework. The back-end is a program running on the 'Ponyland' server park of the Radboud University. It is served through uwsgi. The framework uses a 'model-view-controller' system: the model reflects the structure of the database, the controller determines what is shown to the user when, and the view consists of the HTML files that are served.
The back-end is the place where most of the work takes place for the Passim application. While users are served HTML files, the buttons they press trigger requests to be sent to the server. The Python functions that run there handle the requests and, if needed prepare other HTML pages that are then sent to the user's browser.
The preparation of HTML pages in the Django framework makes use of a template system. The templates contain the rough sketch of the HTML pages, and the data-dependant context provide the information to fill in the details.
The Passim application is first and foremost intended for laptops and computers with a minimum screen size of 1280 pixels.
It is possible to work with Passim from a tablet or smart phone, but there are a couple of things that may not function correctly:
There are no plans right now to make Passim work better on smart phones.
The Passim application uses an SQLite database. This kind of database is contained in one file. This file resides somewhere on the server. Regular back-ups of this file assure little loss of data, should a calamity occur. (Note: the database is a relational one, but it is not a MySQL one.)
The structure of the database can best be seen by glancing through the
models.py file of the Github place where the code is kept.
Each class based on models.Model
represents one table in the database.
The Passim web application allows downloading data in a number of different ways.
Visualizations can also be downloaded, but note that the current visualizations are all quite experimental right now, and not each download function is guaranteed to work as one might want to. We are gradually working on that.
Accessing data by a different program will be made possible in the near future.


--- layout: post title: 'Sony Ericsson''s noddy phones' date: 2005-11-14 00:00:00 categories: business interfaces-&-interaction mobile ---
Sony Ericsson's noddy phones: "Sony Ericsson's big idea, for two of the phones, the J220 and J230, is to include an option that allows the user to customise the interface to make it even simpler to use. They can either opt for the traditional multi icon interface or go for a single icon menu. This enables them to access their core features - and on these phones there aren't a great deal to chose from anyhow – with one click."
Weird.
Firstly, what's in it for a handset manufacturer with a brand of its own to make low-spec devices? Sure, they'll sell more but the margins must be lower on low-end kit using commoditised tech. I can understand why Vodafone want to sell a simple handset - it takes them to a customer-base they might not otherwise reach, which they can then tease into making more use of mobile - but not why SE want to make one.
Secondly - isn't this single-icon/multi-icon menu exactly what Series 40 has been doing for the last few years? I've not seen it, so I can't be sure, but it sounds identical.
Thirdly, it's a mark of how far we've come that a "simple" phone with core features only includes a 128x128 colour screen, calendar, games, and a radio :)
Anyone seen or heard any sales figures for Vodafone Simply btw?


How To Get Rich Quick
Buy the latest and greatest cryptocurrency that no-one has heard of.
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Dear Dry,
Feminist leaders from across the country, including the Feminist Majority Foundation, will be gathering on May 1-3 at the Baltimore Convention Center for *It’s Time 2015: The Partnership Summit to Elevate Women’s Leadership [ http://www.itstime2015.com/events/register/ ]* [ http://www.itstime2015.com/events/register/ ]. Won’t you join us?
This three-day summit features a powerhouse lineup of speakers highlighting how we can advance women’s leadership, empower women and girls, and achieve gender equality – now! *You won’t want to miss it!* [ http://www.itstime2015.com/events/register/ ]
I will be there along with life-long social justice advocate *Dolores Huerta*, founder of the Dolores Huerta Foundation, co-founder of United Farm Workers, FMF Board Member, and Presidential Medal of Freedom recipient.
We will be joined by *Congresswoman Donna Edwards *(D-MD-4); Former First Lady *Rosalynn Carter*; National Organization for Women President *Terry O'Neill*; President and Executive Director of the Lawyers’ Committee for Civil Rights Under Law *Barbara Arnwine*; co-founder of journalist and Executive Producer *Maria Hinojosa*; co-founder of MoveOn.org *Joan Blades*; President and CEO of Girls Inc. *Judy Vredenburgh*; President and CEO of Vital Voices Global Partnership *Alyse Nelson*; and many more.
*Registration is now open [ http://www.itstime2015.com/events/register/ ]* [ http://www.itstime2015.com/events/register/ ]! FMF supporters can use the code *ITSTIMEPARTNER25%* *at this special link* [ http://www.itstime2015.com/events/partner-reg/ ] to receive a 25% discount on a 3-Day All-Access Pass! One-day passes and Student Rates are also *available here* [ http://www.itstime2015.com/events/register/ ].
See you in Baltimore May 1-3! For Equality,
Eleanor Smeal
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FindDoxygen¶
Doxygen is a documentation generation tool (see http://www.doxygen.org).
This module looks for Doxygen and some optional tools it supports. These
tools are enabled as components in the find_package()
command:
dot
- Graphviz
dot
utility used to render various graphs. mscgen
- Message Chart Generator utility used
by Doxygen’s
\msc
and\mscfile
commands. dia
- Dia the diagram editor used by Doxygen’s
\diafile
command.
Examples:
# Require dot, treat the other components as optional
find_package(Doxygen
REQUIRED dot
OPTIONAL_COMPONENTS mscgen dia)
The following variables are defined by this module:
-
DOXYGEN_FOUND
¶ True if the
doxygen
executable was found.
-
DOXYGEN_VERSION
¶ The version reported by
doxygen --version
.
The module defines IMPORTED
targets for Doxygen and each component found.
These can be used as part of custom commands, etc. and should be preferred over
old-style (and now deprecated) variables like DOXYGEN_EXECUTABLE
. The
following import targets are defined if their corresponding executable could be
found (the component import targets will only be defined if that component was
requested):
Doxygen::doxygen
Doxygen::dot
Doxygen::mscgen
Doxygen::dia
Functions¶
-
doxygen_add_docs
¶ This function is intended as a convenience for adding a target for generating documentation with Doxygen. It aims to provide sensible defaults so that projects can generally just provide the input files and directories and that will be sufficient to give sensible results. The function supports the ability to customize the Doxygen configuration used to build the documentation.
doxygen_add_docs(targetName [filesOrDirs...] [ALL] [WORKING_DIRECTORY dir] [COMMENT comment])
The function constructs a
Doxyfile
and defines a custom target that runs Doxygen on that generated file. The listed files and directories are used as theINPUT
of the generatedDoxyfile
and they can contain wildcards. Any files that are listed explicitly will also be added asSOURCES
of the custom target so they will show up in an IDE project’s source list.So that relative input paths work as expected, by default the working directory of the Doxygen command will be the current source directory (i.e.
CMAKE_CURRENT_SOURCE_DIR
). This can be overridden with theWORKING_DIRECTORY
option to change the directory used as the relative base point. Note also that Doxygen’s default behavior is to strip the working directory from relative paths in the generated documentation (see theSTRIP_FROM_PATH
Doxygen config option for details).If provided, the optional
comment
will be passed as theCOMMENT
for theadd_custom_target()
command used to create the custom target internally.If ALL is set, the target will be added to the default build target.
The contents of the generated
Doxyfile
can be customized by setting CMake variables before callingdoxygen_add_docs()
. Any variable with a name of the formDOXYGEN_<tag>
will have its value substituted for the corresponding<tag>
configuration option in theDoxyfile
. See the Doxygen documentation for the full list of supported configuration options.Some of Doxygen’s defaults are overridden to provide more appropriate behavior for a CMake project. Each of the following will be explicitly set unless the variable already has a value before
doxygen_add_docs()
is called (with some exceptions noted):-
DOXYGEN_HAVE_DOT
¶ Set to
YES
if thedot
component was requested and it was found,NO
otherwise. Any existing value ofDOXYGEN_HAVE_DOT
is ignored.
-
DOXYGEN_DOT_MULTI_TARGETS
¶ Set to
YES
by this module (note that this requires adot
version newer than 1.8.10). This option is only meaningful ifDOXYGEN_HAVE_DOT
is also set toYES
.
-
DOXYGEN_GENERATE_LATEX
¶ Set to
NO
by this module.
-
DOXYGEN_WARN_FORMAT
¶ For Visual Studio based generators, this is set to the form recognized by the Visual Studio IDE:
$file($line) : $text
. For all other generators, Doxygen’s default value is not overridden.
-
DOXYGEN_PROJECT_NAME
¶ Populated with the name of the current project (i.e.
PROJECT_NAME
).
-
DOXYGEN_PROJECT_NUMBER
¶ Populated with the version of the current project (i.e.
PROJECT_VERSION
).
-
DOXYGEN_PROJECT_BRIEF
¶ Populated with the description of the current project (i.e.
PROJECT_DESCRIPTION
).
-
DOXYGEN_INPUT
¶ Projects should not set this variable. It will be populated with the set of files and directories passed to
doxygen_add_docs()
, thereby providing consistent behavior with the other built-in commands likeadd_executable()
,add_library()
andadd_custom_target()
. If a variable namedDOXYGEN_INPUT
is set by the project, it will be ignored and a warning will be issued.
-
DOXYGEN_RECURSIVE
¶ Set to
YES
by this module.
-
DOXYGEN_EXCLUDE_PATTERNS
¶ If the set of inputs includes directories, this variable will specify patterns used to exclude files from them. The following patterns are added by
doxygen_add_docs()
to ensure CMake-specific files and directories are not included in the input. If the project setsDOXYGEN_EXCLUDE_PATTERNS
, those contents are merged with these additional patterns rather than replacing them:*/.git/* */.svn/* */.hg/* */CMakeFiles/* */_CPack_Packages/* DartConfiguration.tcl CMakeLists.txt CMakeCache.txt
-
DOXYGEN_OUTPUT_DIRECTORY
¶ Set to
CMAKE_CURRENT_BINARY_DIR
by this module. Note that if the project provides its own value for this and it is a relative path, it will be converted to an absolute path relative to the current binary directory. This is necessary because doxygen will normally be run from a directory within the source tree so that relative source paths work as expected. If this directory does not exist, it will be recursively created prior to executing the doxygen commands.
-
To change any of these defaults or override any other Doxygen config option,
set relevant variables before calling doxygen_add_docs()
. For example:
set(DOXYGEN_GENERATE_HTML NO) set(DOXYGEN_GENERATE_MAN YES) doxygen_add_docs( doxygen ${PROJECT_SOURCE_DIR} COMMENT "Generate man pages" )
A number of Doxygen config options accept lists of values, but Doxygen requires
them to be separated by whitespace. CMake variables hold lists as a string with
items separated by semi-colons, so a conversion needs to be performed. The
doxygen_add_docs()
command specifically checks the following Doxygen config
options and will convert their associated CMake variable’s contents into the
required form if set.
ABBREVIATE_BRIEF
ALIASES
CITE_BIB_FILES
DIAFILE_DIRS
DOTFILE_DIRS
DOT_FONTPATH
ENABLED_SECTIONS
EXAMPLE_PATH
EXAMPLE_PATTERNS
EXCLUDE
EXCLUDE_PATTERNS
EXCLUDE_SYMBOLS
EXPAND_AS_DEFINED
EXTENSION_MAPPING
EXTRA_PACKAGES
EXTRA_SEARCH_MAPPINGS
FILE_PATTERNS
FILTER_PATTERNS
FILTER_SOURCE_PATTERNS
HTML_EXTRA_FILES
HTML_EXTRA_STYLESHEET
IGNORE_PREFIX
IMAGE_PATH
INCLUDE_FILE_PATTERNS
INCLUDE_PATH
INPUT
LATEX_EXTRA_FILES
LATEX_EXTRA_STYLESHEET
MATHJAX_EXTENSIONS
MSCFILE_DIRS
PLANTUML_INCLUDE_PATH
PREDEFINED
QHP_CUST_FILTER_ATTRS
QHP_SECT_FILTER_ATTRS
STRIP_FROM_INC_PATH
STRIP_FROM_PATH
TAGFILES
TCL_SUBST
The following single value Doxygen options will be quoted automatically if they contain at least one space:
CHM_FILE
DIA_PATH
DOCBOOK_OUTPUT
DOCSET_FEEDNAME
DOCSET_PUBLISHER_NAME
DOT_FONTNAME
DOT_PATH
EXTERNAL_SEARCH_ID
FILE_VERSION_FILTER
GENERATE_TAGFILE
HHC_LOCATION
HTML_FOOTER
HTML_HEADER
HTML_OUTPUT
HTML_STYLESHEET
INPUT_FILTER
LATEX_FOOTER
LATEX_HEADER
LATEX_OUTPUT
LAYOUT_FILE
MAN_OUTPUT
MAN_SUBDIR
MATHJAX_CODEFILE
MSCGEN_PATH
OUTPUT_DIRECTORY
PERL_PATH
PLANTUML_JAR_PATH
PROJECT_BRIEF
PROJECT_LOGO
PROJECT_NAME
QCH_FILE
QHG_LOCATION
QHP_CUST_FILTER_NAME
QHP_VIRTUAL_FOLDER
RTF_EXTENSIONS_FILE
RTF_OUTPUT
RTF_STYLESHEET_FILE
SEARCHDATA_FILE
USE_MDFILE_AS_MAINPAGE
WARN_FORMAT
WARN_LOGFILE
XML_OUTPUT
There are situations where it may be undesirable for a particular config option
to be automatically quoted by doxygen_add_docs()
, such as ALIASES
which
may need to include its own embedded quoting. The DOXYGEN_VERBATIM_VARS
variable can be used to specify a list of Doxygen variables (including the
leading DOXYGEN_
prefix) which should not be quoted. The project is then
responsible for ensuring that those variables’ values make sense when placed
directly in the Doxygen input file. In the case of list variables, list items
are still separated by spaces, it is only the automatic quoting that is
skipped. For example, the following allows doxygen_add_docs()
to apply
quoting to DOXYGEN_PROJECT_BRIEF
, but not each item in the
DOXYGEN_ALIASES
list (bracket syntax can also
be used to make working with embedded quotes easier):
set(DOXYGEN_PROJECT_BRIEF "String with spaces")
set(DOXYGEN_ALIASES
[[somealias="@some_command param"]]
"anotherAlias=@foobar"
)
set(DOXYGEN_VERBATIM_VARS DOXYGEN_ALIASES)
The resultant Doxyfile
will contain the following lines:
PROJECT_BRIEF = "String with spaces"
ALIASES = somealias="@some_command param" anotherAlias=@foobar
Deprecated Result Variables¶
For compatibility with previous versions of CMake, the following variables are also defined but they are deprecated and should no longer be used:
-
DOXYGEN_EXECUTABLE
¶ The path to the
doxygen
command. If projects need to refer to thedoxygen
executable directly, they should use theDoxygen::doxygen
import target instead.
-
DOXYGEN_DOT_FOUND
¶ True if the
dot
executable was found.
-
DOXYGEN_DOT_EXECUTABLE
¶ The path to the
dot
command. If projects need to refer to thedot
executable directly, they should use theDoxygen::dot
import target instead.
-
DOXYGEN_DOT_PATH
¶ The path to the directory containing the
dot
executable as reported inDOXYGEN_DOT_EXECUTABLE
. The path may have forward slashes even on Windows and is not suitable for direct substitution into aDoxyfile.in
template. If you need this value, get theIMPORTED_LOCATION
property of theDoxygen::dot
target and useget_filename_component()
to extract the directory part of that path. You may also want to consider usingfile(TO_NATIVE_PATH)
to prepare the path for a Doxygen configuration file.


It uses three important concepts:
interface SimEvent
): an event represents a tuple of a time value
and a corresponding action to be
taken at that time;
interface SimEventAction
): an action to be taken when an event is executed;
interface SimEventList
): a list of events ordered increasing in time,
with unambiguous de-conflicting of simultaneous events.
The SimTimer
class allows convenient scheduling of timer events on an event list.
Example code is available in the example
package.
Last javadoc Review: Jan de Jongh, TNO, 20180404, r5.1.0.


@* * Copyright 2023 HM Revenue & Customs * * Licensed under the Apache License, Version 2.0 (the "License"); * you may not use this file except in compliance with the License. * You may obtain a copy of the License at * * http://www.apache.org/licenses/LICENSE-2.0 * * Unless required by applicable law or agreed to in writing, software * distributed under the License is distributed on an "AS IS" BASIS, * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. * See the License for the specific language governing permissions and * limitations under the License. *@ @import forms.Field @( field: Field, placeholder: String ="", classes: Seq[String] = Seq.empty )(content: Html)(implicit request: Request[_],m:Messages) @if(field.hasErrors) {


{% extends "base.html" %} {% block content %}
{% if invites == [] %}
You currently have no invites.
{% else %}| From: |
Accept? |
|
{{invite.hostId}}
{{invite.date}}
|
{% if inprogress == [] %}
You currently have no games in progress.
{% else %}| Game: |
Turn: |
| {{ipGame.getOpposingPlayer(user)}} | {{ipGame.turn}} |
You don't have any recent games.
{% else %}| Opponent: |
Result: |
| {{games.getOpposingPlayer(user)}} | {{games.getResult(user)}} |


{% extends 'base.html' %} {% load render_bundle from webpack_loader %} {% load crispy_forms_tags %} {% load static %} {% load i18n %} {% block content %}
{% trans "Use this calendar to share conferences, events, and gatherings that you think the P2PU community would be interested in. If you are trying to create a learning circle, " %}{% trans "do that here" %}.
{% endif %}


"Pay It Forward" Noble in Thought but Not in Deed by Homer Yen (c) 2000
In "Pay It Forward" (based on Catherine Ryan Hyde's recent book), a melodrama brimming with cynicism, we see that bad things happen to good people. What's worse, the more good you do, the more you'll get punished for it.
Victimized most by this odd paradox is 7th grader Trevor (Haley Joel Osment). He performs these magnanimous acts of kindness because his erudite Social Studies teacher, Mr. Simonet (Kevin Spacey), has challenged the classroom with an extra credit assignment: "come up with an idea to change our world and put it into action." The unusually benevolent Trevor comes up with a pyramid-like scheme of 'pay-it-forward' where he'll perform an act of kindness for three strangers, and they, in turn, must do the same. But in a cynical world where strangers are more likely to be considered enemies rather than friends, charity is looked upon with suspicion. Even worse, kindness may yield cruel consequences.
Appropriately set in Las Vegas, where losers outnumber winners 20-to-1. "Pay It Forward" makes it clear that the world is full of problems, from wife battering to drug addiction to a wanton need for violence. Yet, amid this chaos, there are glimmers of hope that shine through. This beacon of optimism centers on Trevor and his 'pay it forward' idea. For example, he invites a homeless man (James Caviezel) to come over and sleep in the garage. He also hopes to save his friend from a brutal beating by a group of bullies.
Trevor also tries to make a love match for his mom (Helen Hunt) and Mr. Simonet. Most of the film centers on this plot component. His mom is an irresponsible parent who frequently drinks herself to sleep after pulling double-shifts as a waitress at a strip club. Meanwhile, Mr. Simonet suffers from a scarred psyche that confines him to the prosaic life he now leads. The two are given a chance to explore their pasts, their hopes, and to come to terms with their personal struggles. But their story seems familiar and only partially engaging. Of course, it's a pleasure to watch Hunt and Spacey perform. She gives a gritty and strong performance as the alcoholic mom. Spacey is adept at portraying the vulnerable and wounded man. And Osment shows us that his Oscar-nominated turn in the "Sixth Sense" was no fluke.
But their performances could not hide the film's shortcomings. It's stylistically bland and the screenplay is weak. The story lingers much too long on the Mom/Mr. Simonet element, creating an odd sense of imbalance. With so much of the film focused on this, its original premise becomes supplanted by a love story. It also teases the audience with an idea that it wants to like, but then gets mired in a tone that's continually dispirited and even weepy. The message contained within is that the world is a ball of blighted hope. For Trevor, a mere 12-year old, a small beacon can get easily snuffed out when there is so much to filter through. Consequently, the film tempers its feel-good tone with rejection, sorrow, and defeat. The ending is shamelessly treacly, and whether you'll accept that payoff depends on your tolerance for "Patch Adams." Ultimately, this film presents noble thoughts, but doesn't fulfill its promise.
Grade: B-
S: 1 out of 3 L: 1 out of 3 V: 2 out of 3
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The review above was posted to the
rec.arts.movies.reviews newsgroup (de.rec.film.kritiken for German reviews).
The Internet Movie Database accepts no responsibility for the contents of the
review and has no editorial control. Unless stated otherwise, the copyright
belongs to the author.
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Broken URLs inthe reviews are the responsibility of the author.
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Related links: index of all rec.arts.movies.reviews reviews


size(width, height, unit=px)
Sets the size of the canvas using your preferred measurement scale. If called with just width
& height
values, the canvas will default to using PostScript points for measurement (a.k.a. px
).
If this command is used, it should generally be called at the very beginning of the script. An important exception to this is the use of the export() command as part of a with
statement. In these cases it's perfectly valid to set the size as the first line of the export-block.
If the optional unit
arg is included, it should be one of: px
, pica
, inch
, cm
, or mm
. Setting the canvas's ‘default unit’ in this manner causes all subsequent drawing commands to be interpreted at that scale. The unit types can also be used to multiply values from other systems to the canvas's units. For example 8.5*inch
will always be the width of a letter page (regardless of the canvas's unit).
The dynamic variables WIDTH
and HEIGHT
can be used to obtain the canvas size.
size(20, 20, cm) # the canvas is 20 x 20 cm print(2*inch) >>> 5.079992238900746


class Gem::RequestSet::GemDependencyAPI
A semi-compatible DSL for the Bundler Gemfile and Isolate gem dependencies files.
To work with both the Bundler Gemfile and Isolate formats this implementation takes some liberties to allow compatibility with each, most notably in source.
A basic gem dependencies file will look like the following:
source 'https://rubygems.org' gem 'rails', '3.2.14a gem 'devise', '~> 2.1', '>= 2.1.3' gem 'cancan' gem 'airbrake' gem 'pg'
RubyGems recommends saving this as gem.deps.rb over Gemfile or Isolate.
To install the gems in this Gemfile use `gem install -g` to install it and create a lockfile. The lockfile will ensure that when you make changes to your gem dependencies file a minimum amount of change is made to the dependencies of your gems.
RubyGems can activate all the gems in your dependencies file at startup using the RUBYGEMS_GEMDEPS environment variable or through Gem.use_gemdeps. See Gem.use_gemdeps for details and warnings.
See `gem help install` and `gem help gem_dependencies` for further details.
Attributes
The gems required by gem statements in the gem.deps.rb file
A Hash containing gem names and files to require from those gems.
Public Class Methods
Creates a new GemDependencyAPI that
will add dependencies to the Gem::RequestSet set
based on the
dependency API description in path
.
# File lib/rubygems/request_set/gem_dependency_api.rb, line 193 def initialize set, path @set = set @path = path @current_groups = nil @current_platforms = nil @current_repository = nil @dependencies = {} @default_sources = true @git_set = @set.git_set @git_sources = {} @installing = false @requires = Hash.new { |h, name| h[name] = [] } @vendor_set = @set.vendor_set @source_set = @set.source_set @gem_sources = {} @without_groups = [] git_source :github do |repo_name| repo_name = "#{repo_name}/#{repo_name}" unless repo_name.include? "/" "git://github.com/#{repo_name}.git" end git_source :bitbucket do |repo_name| repo_name = "#{repo_name}/#{repo_name}" unless repo_name.include? "/" user, = repo_name.split "/", 2<EMAIL_ADDRESS>end end
Public Instance Methods
Defines a custom git source that uses name
to expand git
repositories for use in gems built from git repositories. You must provide
a block that accepts a git repository name for expansion.
# File lib/rubygems/request_set/gem_dependency_api.rb, line 603 def git_source name, &callback @git_sources[name] = callback end
Loads the gem dependency file and returns self.
# File lib/rubygems/request_set/gem_dependency_api.rb, line 278 def load instance_eval File.read(@path).untaint, @path, 1 self end
Private Instance Methods
Pins the gem name
to the given source
. Adding a
gem with the same name from a different source
will raise an
exception.
# File lib/rubygems/request_set/gem_dependency_api.rb, line 694 def pin_gem_source name, type = :default, source = nil source_description = case type when :default then '(default)' when :path then "path: #{source}" when :git then "git: #{source}" when :source then "source: #{source}" else '(unknown)' end raise ArgumentError, "duplicate source #{source_description} for gem #{name}" if @gem_sources.fetch(name, source) != source @gem_sources[name] = source end
Gem Dependencies DSL
↑ topPublic Instance Methods
Specifies a gem dependency with the given name
and
requirements
. You may also supply options
following the requirements
options
include:
- require:
-
RubyGems does not provide any autorequire features so requires in a gem dependencies file are recorded but ignored.
In bundler the require: option overrides the file to require during Bundler.require. By default the name of the dependency is required in Bundler. A single file or an Array of files may be given.
To disable requiring any file give
false
:gem 'rake', require: false
- group:
-
Place the dependencies in the given dependency group. A single group or an Array of groups may be given.
See also group
- platform:
-
Only install the dependency on the given platform. A single platform or an Array of platforms may be given.
See platform for a list of platforms available.
- path:
-
Install this dependency from an unpacked gem in the given directory.
gem 'modified_gem', path: 'vendor/modified_gem'
- git:
-
Install this dependency from a git repository:
gem 'private_gem', git: git@my.company.example:private_gem.git'
- gist:
-
Install this dependency from the gist ID:
gem 'bang', gist: '1232884'
- github:
-
Install this dependency from a github git repository:
gem 'private_gem', github: 'my_company/private_gem'
- submodules:
-
Set to
true
to include submodules when fetching the git repository for git:, gist: and github: dependencies. - ref:
-
Use the given commit name or SHA for git:, gist: and github: dependencies.
- branch:
-
Use the given branch for git:, gist: and github: dependencies.
- tag:
-
Use the given tag for git:, gist: and github: dependencies.
# File lib/rubygems/request_set/gem_dependency_api.rb, line 355 def gem name, *requirements options = requirements.pop if requirements.last.kind_of?(Hash) options ||= {} options[:git] = @current_repository if @current_repository source_set = false source_set ||= gem_path name, options source_set ||= gem_git name, options source_set ||= gem_git_source name, options source_set ||= gem_source name, options duplicate = @dependencies.include? name @dependencies[name] = if requirements.empty? and not source_set then Gem::Requirement.default elsif source_set then Gem::Requirement.source_set else Gem::Requirement.create requirements end return unless gem_platforms options groups = gem_group name, options return unless (groups & @without_groups).empty? pin_gem_source name, :default unless source_set gem_requires name, options if duplicate then warn <<-WARNING Gem dependencies file #{@path} requires #{name} more than once. WARNING end @set.gem name, *requirements end
Loads dependencies from a gemspec file.
options
include:
- name:
-
The name portion of the gemspec file. Defaults to searching for any gemspec file in the current directory.
gemspec name: 'my_gem'
- path:
-
The path the gemspec lives in. Defaults to the current directory:
gemspec 'my_gem', path: 'gemspecs', name: 'my_gem'
- development_group:
-
The group to add development dependencies to. By default this is :development. Only one group may be specified.
# File lib/rubygems/request_set/gem_dependency_api.rb, line 636 def gemspec options = {} name = options.delete(:name) || '{,*}' path = options.delete(:path) || '.' development_group = options.delete(:development_group) || :development spec = find_gemspec name, path groups = gem_group spec.name, {} self_dep = Gem::Dependency.new spec.name, spec.version add_dependencies groups, [self_dep] add_dependencies groups, spec.runtime_dependencies @dependencies[spec.name] = Gem::Requirement.source_set spec.dependencies.each do |dep| @dependencies[dep.name] = dep.requirement end groups << development_group add_dependencies groups, spec.development_dependencies @vendor_set.add_vendor_gem spec.name, path gem_requires spec.name, options end
Block form for specifying gems from a git repository
.
git 'https://github.com/rails/rails.git' do gem 'activesupport' gem 'activerecord' end
# File lib/rubygems/request_set/gem_dependency_api.rb, line 589 def git repository @current_repository = repository yield ensure @current_repository = nil end
Block form for placing a dependency in the given groups
.
group :development do gem 'debugger' end group :development, :test do gem 'minitest' end
Groups can be excluded at install time using `gem install -g –without development`. See `gem help install` and `gem help gem_dependencies` for further details.
# File lib/rubygems/request_set/gem_dependency_api.rb, line 681 def group *groups @current_groups = groups yield ensure @current_groups = nil end
Block form for restricting gems to a set of platforms.
The gem dependencies platform is different from Gem::Platform. A platform gem.deps.rb platform matches on the ruby engine, the ruby version and whether or not windows is allowed.
- :ruby, :ruby_XY
-
Matches non-windows, non-jruby implementations where X and Y can be used to match releases in the 1.8, 1.9, 2.0 or 2.1 series.
- :mri, :mri_XY
-
Matches non-windows C Ruby (Matz Ruby) or only the 1.8, 1.9, 2.0 or 2.1 series.
- :mingw, :mingw_XY
-
Matches 32 bit C Ruby on MinGW or only the 1.8, 1.9, 2.0 or 2.1 series.
- :x64_mingw, :x64_mingw_XY
-
Matches 64 bit C Ruby on MinGW or only the 1.8, 1.9, 2.0 or 2.1 series.
- :mswin, :mswin_XY
-
Matches 32 bit C Ruby on Microsoft Windows or only the 1.8, 1.9, 2.0 or 2.1 series.
- :mswin64, :mswin64_XY
-
Matches 64 bit C Ruby on Microsoft Windows or only the 1.8, 1.9, 2.0 or 2.1 series.
- :jruby, :jruby_XY
-
Matches JRuby or JRuby in 1.8 or 1.9 mode.
- :maglev
-
Matches Maglev
- :rbx
-
Matches non-windows Rubinius
NOTE: There is inconsistency in what environment a platform matches. You may need to read the source to know the exact details.
# File lib/rubygems/request_set/gem_dependency_api.rb, line 756 def platform *platforms @current_platforms = platforms yield ensure @current_platforms = nil end
Block form for restricting gems to a particular set of platforms. See platform.
Restricts this gem dependencies file to the given ruby
version
.
You may also provide engine:
and engine_version:
options to restrict this gem dependencies file to a particular ruby engine
and its engine version. This matching is performed by using the
RUBY_ENGINE and engine_specific VERSION constants. (For JRuby,
JRUBY_VERSION).
# File lib/rubygems/request_set/gem_dependency_api.rb, line 783 def ruby version, options = {} engine = options[:engine] engine_version = options[:engine_version] raise ArgumentError, 'you must specify engine_version along with the ruby engine' if engine and not engine_version return true if @installing unless RUBY_VERSION == version then message = "Your Ruby version is #{RUBY_VERSION}, " + "but your #{gem_deps_file} requires #{version}" raise Gem::RubyVersionMismatch, message end if engine and engine != Gem.ruby_engine then message = "Your ruby engine is #{Gem.ruby_engine}, " + "but your #{gem_deps_file} requires #{engine}" raise Gem::RubyVersionMismatch, message end if engine_version then my_engine_version = Object.const_get "#{Gem.ruby_engine.upcase}_VERSION" if engine_version != my_engine_version then message = "Your ruby engine version is #{Gem.ruby_engine} #{my_engine_version}, " + "but your #{gem_deps_file} requires #{engine} #{engine_version}" raise Gem::RubyVersionMismatch, message end end return true end
Sets url
as a source for gems for this dependency API.
RubyGems uses the default configured sources if no source was given. If a
source is set only that source is used.
This method differs in behavior from Bundler:
-
The
:gemcutter
, #:rubygems
and:rubyforge
sources are not supported as they are deprecated in bundler. -
The
prepend:
option is not supported. If you wish to order sources then list them in your preferred order.
# File lib/rubygems/request_set/gem_dependency_api.rb, line 836 def source url Gem.sources.clear if @default_sources @default_sources = false Gem.sources << url end


Product Brief: title
tl;dr: XYZ.
the product:
hackmd.io
the competition:
XYZ
proposals:
-
ordered list of XYZ
-
XYZ
-
XYZ
monetize it:
-
ordered list of XYZ
-
XYZ
-
XYZ
in which I discuss ideas to improve or next-step products, write about technical people writing, and ramble about life
tl;dr: XYZ.
hackmd.io
XYZ
ordered list of XYZ
XYZ
XYZ
ordered list of XYZ
XYZ
XYZ


Cucumber.js is available as an npm module.
Install globally with:
$ npm install -g cucumber
OR
You may also define cucumber.js as a development dependency of your application by including it in your package.json
file.
{
"devDependencies": {
"cucumber": "latest"
}
}
Then install with npm install --dev
You can find more information in cucumber-js


I'm writing this because I'm suddenly afraid of dying.
I can explain where is this coming from, but explaining does not give meaning to the fact that I'm scared at the possibility of something that is going to happen. For sure, it is going to happen. To me and to everyone else.
Our shared experience.
I have no idea if writing about it makes me feel safer or not. Or why, if I'm truly scared, writing here makes sense.
Shouldn't I be making amends and sending messages telling people I love them?
Legacy, meaning, purpose. What does that mean?
There isn't a point for this post.
But I am going to use it as a reminder of mortality, of being present everyday, of the very fragile nature of being human and as a thank you to the universe, to my parents, and to the blobs of energy that came together to form the human that is writing on the other side of the screen.


TBuffer class
property Name: TBuffString;
The property Name gets and sets the name of the buffer.
Usually this would be the URL or filename of the buffer.


Set availability status to give assessments to your peers. When your Assessment Availability is ON, you will start receiving assessment requests from your peers. Available for assessments?