Timing the Emergence of Resistance to Anti-HIV Drugs with Large Genetic Barriers

New antiretroviral drugs that offer large genetic barriers to resistance, such as the recently approved inhibitors of HIV-1 protease, tipranavir and darunavir, present promising weapons to avert the failure of current therapies for HIV infection. Optimal treatment strategies with the new drugs, however, are yet to be established. A key limitation is the poor understanding of the process by which HIV surmounts large genetic barriers to resistance. Extant models of HIV dynamics are predicated on the predominance of deterministic forces underlying the emergence of resistant genomes. In contrast, stochastic forces may dominate, especially when the genetic barrier is large, and delay the emergence of resistant genomes. We develop a mathematical model of HIV dynamics under the influence of an antiretroviral drug to predict the waiting time for the emergence of genomes that carry the requisite mutations to overcome the genetic barrier of the drug. We apply our model to describe the development of resistance to tipranavir in in vitro serial passage experiments. Model predictions of the times of emergence of different mutant genomes with increasing resistance to tipranavir are in quantitative agreement with experiments, indicating that our model captures the dynamics of the development of resistance to antiretroviral drugs accurately. Further, model predictions provide insights into the influence of underlying evolutionary processes such as recombination on the development of resistance, and suggest guidelines for drug design: drugs that offer large genetic barriers to resistance with resistance sites tightly localized on the viral genome and exhibiting positive epistatic interactions maximally inhibit the emergence of resistant genomes.

Timing of weaning and processing: effects on liveweight changes of weaner cattle

To reduce the number of musters and handling costs, calves in extensive cattle herds in northern Australia are processed (vaccinated, ear-marked, de-horned, branded and males castrated) shortly after they are weaned. As stress has adverse effects on health and growth, and weaning is a stressful time for calves, this experiment asked if calf health, welfare and performance were improved when calves had a period with their mothers post-processing, before they were weaned.

Timing of fungicide applications for control of husk spot caused by Pseudocercospora macadamiae in macadamia

Pseudocercospora macadamiae is an important pathogen of macadamia in Australia, causing a disease known as husk spot. Growers strive to control the disease with a number of carbendazim and copper treatments. The aim of this study was to consider the macadamia fruit developmental stage at which fungicide application is most effective against husk spot, and whether application of copper-only applications at full-size fruit developmental stage toward the end of the season contributed to effective disease control. Fungicides were applied to macadamia trees at four developmental stages in three orchards in two subsequent production seasons. The effects of the treatments on disease incidence and severity were quantified using area under disease progress curve (AUDPC) and logistic regression models. Although disease incidence varied between cultivars, incidence and severity on cv. A16 showed consistent differences between the treatments. Most significant reduction in husk spot incidence occurred when spraying commenced at match-head sized-fruit developmental stage. All treatments significantly reduced husk spot incidence and severity compared with the untreated controls, and a significant positive linear relationship (R2 = 73%) between AUDPC and severity showed that timing of the first fungicide application is important for effective disease control. Application of fungicide at full-size fruit stage reduced disease incidence but had no impact on premature fruit drop.

Effect of timing of a deficit-irrigation allocation on corn evapotranspiration, yield, water use efficiency and dry mass

Water regulations have decreased irrigation water supplies in Nebraska and some other areas of the USA Great Plains. When available water is not enough to meet crop water requirements during the entire growing cycle, it becomes critical to know the proper irrigation timing that would maximize yields and profits. This study evaluated the effect of timing of a deficit-irrigation allocation (150 mm) on crop evapotranspiration (ETc), yield, water use efficiency (WUE = yield/ETc), irrigation water use efficiency (IWUE = yield/irrigation), and dry mass (DM) of corn (Zea mays L.) irrigated with subsurface drip irrigation in the semiarid climate of North Platte, NE. During 2005 and 2006, a total of sixteen irrigation treatments (eight each year) were evaluated, which received different percentages of the water allocation during July, August, and September. During both years, all treatments resulted in no crop stress during the vegetative period and stress during the reproductive stages, which affected ETc, DM, yield, WUE and IWUE. Among treatments, ETc varied by 7.2 and 18.8%; yield by 17 and 33%; WUE by 12 and 22%, and IWUE by 18 and 33% in 2005 and 2006, respectively. Yield and WUE both increased linearly with ETc and with ETc/ETp (ETp = seasonal ETc with no water stress), and WUE increased linearly with yield. The yield response factor (ky) averaged 1.50 over the two seasons. Irrigation timing affected the DM of the plant, grain, and cob, but not that of the stover. It also affected the percent of DM partitioned to the grain (harvest index), which increased linearly with ETc and averaged 56.2% over the two seasons, but did not affect the percent allocated to the cob or stover. Irrigation applied in July had the highest positive coefficient of determination (R2) with yield. This high positive correlation decreased considerably for irrigation applied in August, and became negative for irrigation applied in September. The best positive correlation between the soil water deficit factor (Ks) and yield occurred during weeks 12-14 from crop emergence, during the "milk" and "dough" growth stages. Yield was poorly correlated to stress during weeks 15 and 16, and the correlation became negative after week 17. Dividing the 150 mm allocation about evenly among July, August and September was a good strategy resulting in the highest yields in 2005, but not in 2006. Applying a larger proportion of the allocation in July was a good strategy during both years, and the opposite resulted when applying a large proportion of the allocation in September. The different results obtained between years indicate that flexible irrigation scheduling techniques should be adopted, rather than relying on fixed timing strategies.

Influence of validation schemes in a laser Doppler anemometer period timing device for frequency measurement

The short duration of the Doppler signal and noise content in it necessitate a validation scheme to be incorporated in the electronic processor used for frequency measurement, There are several different validation schemes that can be employed in period timing devices. A detailed study of the influence of these validation schemes on the measured frequency has been reported here. These studies were carried out by using a combination of a fast A/D converter and computer. Doppler bursts obtained from an air flow were digitised and stored on magnetic discs. Suitable computer programs were then used to simulate the performance of period timing devices with different validation schemes and the frequency of the stored bursts were evaluated. It is found that best results are obtained when the validation scheme enables frequency measurement to be made over a large number of cycles within the burst.

Timing of infection of macadamia fruit by Pseudocercospora macadamiae and climatic effects on growth and spore germination.

Pseudocercospora macadamiae causes husk spot of macadamia. Husk spot control would be improved by verifying the stages in fruit development susceptible to infection, and determine some of the climatic conditions likely to lead to high disease pressure periods in the field. Our results showed that the percent conidia germination and growth of germ tubes and mycelia of P. macadamiae were greatest at 26 degrees C, with better conidia germination associated with high relative humidity and free water. The exposure of match-head-sized and pea-sized fruit stages to natural P. macadamiae inoculum in the field led to 2 5-fold increases in husk spot incidence, and up to 8.5-fold increases in premature abscission, compared with unexposed fruit. Exposure of fruit stages later than match-head-sized and pea-sized fruit generally caused no further increases in disease incidence or premature abscission. Climatic conditions were found to have a strong influence on the behaviour of P. macadamiae, the host, oil accumulation, and the subsequent impact of husk spot on premature abscission. Our findings suggest that fungicide application should target fruit at the match-head-sized stage of development in order to best reduce yield losses, particularly in seasons where oil accumulation in fruit is prolonged and climatic conditions are optimal for P. macadamiae.

Simple period timing device for laser Doppler signals

A period timing device suitable for processing laser Doppler anemometer signals has been described here. The important features of this instrument are: it is inexpensive, simple to operate, and easy to fabricate. When the concentration of scattering particles is low the Doppler signal is in the form of a burst and the Doppler frequency is measured by timing the zero crossings of the signal. But the presence of noise calls for the use of validation criterion, and a 5–8 cycles comparison has been used in this instrument. Validation criterion requires the differential count between the 5 and 8 cycles to be multiplied by predetermined numbers that prescribe the accuracy of measurement. By choosing these numbers to be binary numbers, much simplification in circuit design has been accomplished since this permits the use of shift registers for multiplication. Validation accuracies of 1.6%, 3.2%, 6.3%, and 12.5% are possible with this device. The design presented here is for a 16-bit processor and uses TTL components. By substituting Schottky barrier TTLs the clock frequency can be increased from about 10 to 30 MHz resulting in an extension in the range of the instrument. Review of Scientific Instruments is copyrighted by The American Institute of Physics.

Effects of seed origin latitude on the timing of height growth cessation and field performance of silver birch

The aim of this thesis was to increase our knowledge about the effects of seed origin on the timing of height growth cessation and field performance of silver birch from different latitudes, with special attention paid to the browsing damage by moose in young birch plantations. The effect of seed origin latitude and sowing time on timing of height growth cessation of first-year seedlings was studied in a greenhouse experiment with seven seed origins (lat. 58º - 67ºN). Variation in critical night length (CNL) for 50 % bud set within two latitudinally distant stands (60º and 67ºN) was studied in three phytotron experiments. Browsing by moose on 5-11 -year-old silver birch saplings from latitudinally different seed origins (53º - 67ºN) was studied in a field experiment in southern Finland. Yield and stem quality of 22-year-old silver birch trees of Baltic, Finnish and Russian origin (54º - 63ºN) and the effect of latitudinal seed transfers were studied in two provenance trials at Tuusula, southern and Viitasaari, central Finland. The timing of height growth cessation depended systematically on latitude of seed origin and sowing date. The more northern the seed origin, the earlier the growth cessation and the shorter the growth period. Later sowing dates delayed growth cessation but also shortened the growth period. The mean CNL of the southern ecotype was longer, 6.3 ± 0.2 h (95 % confidence interval), than that of the northern ecotype, 3.1 ± 0.3 h. Within-ecotype variance of the CNL was higher in the northern ecotype (0.484 h2) than in the southern ecotype (0.150 h2). Browsing by moose decreased with increasing latitude of seed origin and sapling height. Origins transferred from more southern latitudes were more heavily browsed than the more northern native ones. Southern Finnish seed origins produced the highest volume per unit area in central Finland (lat. 63º11'N). Estonian and north Latvian stand seed origins, and the southern Finnish plus tree origins, were the most productive ones in southern Finland (lat. 60º21'N). Latitudinal seed transfer distance had a significant effect on survival, stem volume/ha and proportion of trees with a stem defect. The relationship of both survival and stem volume/ha to the latitudinal seed transfer distance was curvilinear. Volume was increased by transferring seed from ca. 2 degrees of latitude from the south. A longer transfer from the south, and transfer from the north, decreased the yield. The proportion of trees with a stem defect increased linearly in relation to the latitudinal seed transfer distance from the south.

Timing of Infection and Development of Alternaria Diseases in the Canopy of Apple Trees

Alternaria leaf blotch and fruit spot of apple caused by Alternaria spp. cause annual losses to the Australian apple industry. Erratic control using protectant fungicides is often experienced and may be due to the lack of understanding of the timing of infection and epidemiology of the diseases. We found that Alternaria leaf blotch infection began about 20 days after bloom (DAB) and the highest disease incidence occurred from 70 to 110 DAB. Alternaria fruit spot infection occurred about 100 DAB in the orchard. Fruit inoculations in planta showed that there was no specific susceptible stage of fruit. Leaves and fruit in the lower canopy of trees showed higher levels of leaf blotch and fruit spot incidence than those in the upper canopy and the incidence of leaf blotch in shoot leaves was higher than in spur leaves. Temperature, relative humidity, and rainfall affected leaf blotch and fruit spot incidence. The gained knowledge on the timing of infection and development of disease may aid in the development of more effective disease management strategies.

Simple period timing device for laser Doppler signals

A period timing device suitable for processing laser Doppler anemometer signals has been described here. The important features of this instrument are: it is inexpensive, simple to operate, and easy to fabricate. When the concentration of scattering particles is low the Doppler signal is in the form of a burst and the Doppler frequency is measured by timing the zero crossings of the signal. But the presence of noise calls for the use of validation criterion, and a 5–8 cycles comparison has been used in this instrument. Validation criterion requires the differential count between the 5 and 8 cycles to be multiplied by predetermined numbers that prescribe the accuracy of measurement. By choosing these numbers to be binary numbers, much simplification in circuit design has been accomplished since this permits the use of shift registers for multiplication. Validation accuracies of 1.6%, 3.2%, 6.3%, and 12.5% are possible with this device. The design presented here is for a 16-bit processor and uses TTL components. By substituting Schottky barrier TTLs the clock frequency can be increased from about 10 to 30 MHz resulting in an extension in the range of the instrument. Review of Scientific Instruments is copyrighted by The American Institute of Physics.

Timing of puberty : Genetic regulation

In the general population, the timing of puberty is normally distributed. This variation is determined by genetic and environmental factors, but the exact mechanisms underlying these influences remain elusive. The purpose of this study was to gain insight into genetic regulation of pubertal timing. Contributions of genetic versus environmental factors to the normal variation of pubertal timing were explored in twins. Familial occurrence and inheritance patterns of constitutional delay of growth and puberty, CDGP (a variant of normal pubertal timing), were studied in pedigrees of patients with this condition. To ultimately detect genes involved in the regulation of pubertal timing, genetic loci conferring susceptibility to CDGP were mapped by linkage analysis in the same family cohort. To subdivide the overall phenotypic variance of pubertal timing into genetic and environmental components, genetic modeling based on monozygous twins sharing 100% and dizygous twins sharing 50% of their genes was used in 2309 girls and 1828 boys from the FinnTwin 12-17 study. The timing of puberty was estimated from height growth, i.e. change in the relative height between the age when pubertal growth velocity peaks in the general population and adulthood. This reflects the percentage of adult height achieved at the average peak height velocity age, and thus, pubertal timing. Boys and girls diagnosed with CDGP were gathered through medical records from six pediatric clinics in Finland. First-degree relatives of the probands were invited to participate by letter; altogether, 286 families were recruited. When possible, families were extended to include also second-, third-, or fourth-degree relatives. The timing of puberty in all family members was primarily assessed from longitudinal growth data. Delayed puberty was defined by onset of pubertal growth spurt or peak height velocity taking place 1.5 (relaxed criterion) or 2 SD (strict criterion) beyond the mean. If growth data were unavailable, pubertal timing was based on interviews. In this case, CDGP criteria were set as having undergone pubertal development more than 2 (strict criterion) or 1.5 years (relaxed criterion) later than their peers, or menarche after 15 (strict criterion) or 14 years (relaxed criterion). Familial occurrence of strict CDGP was explored in families of 124 patients (95 males and 29 females) from two clinics in Southern Finland. In linkage analysis, we used relaxed CDGP criteria; 52 families with solely growth data-based CDGP diagnoses were selected from all clinics. Based on twin data, genetic factors explain 86% and 82% of the variance of pubertal timing in girls and boys, respectively. In families, 80% of male and 76% of female probands had affected first-degree relatives, in whom CDGP was 15 times more common than the expected (2.5%). In 74% (17 of 23) of the extended families with only one affected parent, familial patterns were consistent with autosomal dominant inheritance. By using 383 multiallelic markers and subsequently fine-mapping with 25 additional markers, significant linkage for CDGP was detected to the pericentromeric region of chromosome 2, to 2p13-2q13 (multipoint HLOD 4.44, α 0.41). The findings of the large twin study imply that the vast majority of the normal variation of pubertal timing is attributed to genetic effects. Moreover, the high frequency of dominant inheritance patterns and the large number of affected relatives of CDGP patients suggest that genetic factors also markedly contribute to constitutional delay of puberty. Detection of the locus 2p13-2q13 in the pericentromeric region of chromosome 2 associating with CDGP is one step towards unraveling the genes that determine pubertal timing.

SIR Analysis and Interference Cancellation in Uplink OFDMA with Large Carrier Frequency/Timing Offsets

In uplink OFDMA, carrier frequency offsets (CFO) and/or timing offsets (TO) of other users with respect to a desired user can cause multiuser interference (MUI). In practical uplink OFDMA systems (e.g., IEEE 802.16e standard), effect of this MUI is made acceptably small by requiring that frequency/timing alignment be achieved at the receiver with high precision (e.g., CFO must be within 1 % of the subcarrier spacing and TO must be within 1/8th of the cyclic prefix duration in IEEE 802.16e), which is realized using complex closed-loop frequency/timing correction between the transmitter and the receiver. An alternate open-loop approach to handle the MUI induced by large CFOs and TOs is to employ interference cancellation techniques at the receiver. In this paper, we first analytically characterize the degradation in the average output signal-to-interference ratio (SIR) due to the combined effect of large CFOs and TOs in uplink OFDMA. We then propose a parallel interference canceller (PIC) for the mitigation of interference due to CFOs and TOs in this system. We show that the proposed PIC effectively mitigates the performance loss due to CFO/TO induced interference in uplink OFDMA.