Synthesis and Antiviral Properties of Arabino and Ribonucleosides of 1,3‐Dideazaadenine, 4‐Nitro‐1, 3‐dideazaadenine and Diketopiperazine

Different arabinosides and ribosides, viz. Ara‐DDA or 9(1‐β‐d‐arabinofuranosyl) 1,3‐dideazaadenine (6), Ara‐NDDP or 9(1‐β‐d‐arabinofuranosyl) 4‐nitro‐1,3‐dideazapurine (7), Ara‐DKP or 1(1‐β‐d‐arabinofuranosyl) diketopiperazine (8), Ribo‐DDA or 9(1‐β‐d‐ribofuranosyl) 1,3‐dideazaadenine (9) and Ribo‐NDDP or 9(1‐β‐d‐ribofuranosyl) 4‐nitro‐1,3‐dideazapurine (10) have been synthesized as probable antiviral agents. The arabinosides have been synthesized using the catalyst TDA‐1 that causes stereospecific formation of β‐nucleosides while a one‐pot synthesis procedure was adopted for the synthesis of the ribonucleosides where β‐anomers were obtained in higher yields. All the five nucleoside analogs have been screened for antiviral property against HIV‐1 (III_B), HSV‐1 and 2, parainfluenza‐3, reovirus‐1 and many others. It was observed that arabinosides had greater inhibitory action than ribosides. The compound 7 or Ara‐NDDP has shown maximum inhibition of HIV‐1 replication than the rest of the molecules with an IC₅₀ of 79.4 µg/mL.     

Design,Efficient Synthesis,and Anti‐HIV Activity of 4′‐C‐Cyano‐ and 4′‐C‐Ethynyl‐2′‐deoxy Purine Nucleosides

Some 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides showed the most potent anti‐HIV activity among the series of 4′‐C‐substituted 2′‐deoxynucleosides whose 4′‐C‐substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C‐4′ position they have, the more acceptable biological activity they show. Thus, 4′‐C‐cyano‐2′‐deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4′‐C‐cyano‐2′‐deoxy purine nucleosides (4′‐CNdNs) and 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides (4′‐EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2′‐deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C‐4′ position of the sugar moiety from 2′‐deoxyadenosine and 2,6‐diaminopurine 2′‐deoxyriboside. Unfortunately, 4′‐C‐cyano derivatives showed lower activity against HIV‐1, and two 4′‐C‐ethynyl derivatives suggested high toxicity in vivo.     

Thiosugar Nucleosides. Synthesis and Biological Activity of 1,3,4‐Thiadiazole,Thiazoline and Thiourea Derivatives of 5‐Thio‐d‐Glucose

New acylated 5‐thio‐β‐d‐glucopyranosylimino‐disusbstituted 1,3,4‐thiadiazols 8, and 11 were prepared, via spontaneous rearrangements, by cycloaddition of the glycosyl isothiocyanate 2 with the reactive intermediates 1‐aza‐2‐azoniaallene hexachloroantimonates 4 and 6, respectively. Reaction of 2 with aminoacetone or chloroethylamine afforded the acylated 5‐thio‐β‐d‐glucopyranosyl‐4‐imidazoline‐2‐thione nucleoside 16 and glucopyranosylamino‐2‐thiazoline derivative 18, respectively. Deblocking of 8, 11, 17 and 19 furnished the free nucleoside analogues 9, 12, 18 and 20, respectively. Analogously, treatment of 2 with chloroethylamine in the 1:2 ratio afforded the thioureylendisaccharide 21. No in vitro antiviral activity against HIV‐1, HIV‐2, human cytomegallovirus (HMCV), has been found for the new synthesized compounds.     

The season‐of‐birth paradox

Abstract

Vital statistics data show a remarkably consistent seasonality in U.S. birth patterns, with peaks in late summer and winter months, and a valley in the spring. An attitude survey of college students suggests that peaks in the actual birth distribution occur in unpopular months in which to give birth; the valley in the actual birth distribution occurs in popular months. This paradoxical finding is named the Season‐of‐Birth Paradox. Explanations to resolve the paradox include biological and psychological components. A psychological mechanism—named the Misinformed Reproducer Hypothesis—is tested using NSFG data from the 1973–75 and 1979–81 cycles. Results suggest that women stop contracepting with the expectation that they will get pregnant almost immediately. When it takes several months on the average for a successful conception to occur, the actual birth distribution is shifted away from the preferred birth distribution. These results suggest that psychological as well as biological mechanisms underlie the consistent seasonality patterns in U.S. births.     

Effect of Time of Day and Partial Sleep Deprivation on Short‐Term,High‐Power Output

The purpose of this study was to determine whether delaying bedtime or advancing rising time by 4 h affects anaerobic performance of individuals the following day in the morning and afternoon. Eleven subjects participated in the study, during which we measured the maximal, peak, and mean powers (i.e., P_max [force‐velocity test], P_peak, and P_mean [Wingate test], respectively). Measurements were performed twice daily, at 07∶00 and 18∶00 h, following a reference normal sleep night (RN), a partial sleep deprivation timed at the beginning of the night (SDB), and a partial sleep deprivation timed at the end of the night (SDE), and oral temperature was measured every 4 h. Each of the three experimental conditions was separated by a one‐week period. Our results showed a circadian rhythm in oral temperature, and analysis of variance revealed a significant sleep×test‐time effect on peak power (P_peak), mean power (P_mean), and maximal power (P_max). These variables improved significantly from the morning to the afternoon for all three experimental conditions. Whereas the morning‐afternoon improvement in the measures was similar after the RN and SDB conditions, it was smaller following the SDE condition. There was no significant difference in the effect of the two sleep‐deprivation conditions on anaerobic performances at 07∶00 and at 18∶00 h under the SDB condition in comparison with the post‐reference night. However, the performance variables were significantly lower at 18∶00 h after the SDE condition. In conclusion, a 4 h partial sleep deprivation at the end of the night appears to be more disturbing than partial sleep deprivation at the beginning of the night.     

Density‐dependent parasitism in biological control of soil‐borne insects,nematodes, fungi and bacteria

Temporal density‐dependent parasitism appears to explain the development of some pest‐ and pathogen‐suppressive soils. In many examples, an enrichment of hosts (soil‐borne pests or pathogens) precedes and supports a build up of beneficial parasites in perennial crops or in monocultures, and the population dynamics of hosts and parasites may be described in epidemiological terms. Although the examples support the concept of a balance of nature based on density‐dependent regulation, we lack detailed understanding of the processes that drive these beneficial epidemics. In addition, the epidemics develop slowly and often do not provide the control expected by farmers. Current research, therefore, emphasizes inundative release of beneficial agents. Nevertheless, we should study epidemics in soil in order to learn how they might be enhanced; to learn how better to utilize inoculum that is inundatively added to soil; and to contribute to the general discussion of population biology and regulation.     

Age‐Related Differences in the Lifestyle Regularity of Seniors Experiencing Bereavement,Care‐Giving,Insomnia, and Advancement Into Old‐Old Age

Compared to younger adults, seniors (≥60 yrs) often adopt a highly regular lifestyle, perhaps as an adaptive response to age‐related changes in their sleep and circadian rhythms. At baseline, diary measures of lifestyle regularity (SRM‐5) were obtained from 104 seniors of three separate groups. Thirty‐three subjects were challenged by spousal bereavement or the need to care for a spouse at home with dementia (Challenged); 33 were suffering from formally diagnosed (DSM‐IV) insomnia (Insomnia); and 38 were healthy, well‐functioning older seniors in the second half of their eighth decade of life or later (Healthy Older). The objective of this study was to determine whether lifestyle regularity increased as a function of age within each of these three senior groups. Overall, age was significantly correlated with SRM‐5 (r=0.41, p<0.001), with the SRM score increasing by 0.67 units/decade. The same was true for the Challenged and Insomnia groups, which also showed a significant correlation between SRM and age (Challenged: r=0.48, p<0.01; Insomnia: r=0.36, p<0.05), though with a slightly faster rate of SRM increase in the Challenged (0.95 units/decade) than Insomnia (0.55 units/decade) group. Perhaps there was no correlation between age and SRM (r=0.07, n.s.) in the Healthy Older group due to the small age range, although this group did have a higher overall SRM score than the other two groups (p<0.01). The study thus confirmed that the previously observed increase in lifestyle regularity over the adult lifespan persists into later life. This may represent an adaptive behavioral response that might be used in future therapeutic approaches.     

Litho‐diagenetic implications of the calcium oxalate‐carbonate biogeochemical cycle in semiarid Calcretes,Nazareth, Israel

Microscopic observations of calcrete soil samples in semiarid environments from Israel reveal a particular vesicular microfabric. The calcrete horizon is indurated but highly porous and all the pores are coated with a gray layer (quasi‐coating) of secondary calcium carbonate. Two kinds of needles are found inside the pores: thin and regular needles (calcite), and filaments with very sharp spikes that are of fungal origin. Analysis of the proportions of C, O, and Ca were made with an E.D.S. microprobe connected with a scanning electron microscope to distinguish calcite (CaCO₃) from calcium oxalate (CaC₂O₄) and to differentiate inorganic from organic influences. Under biological control, calcium oxalate coexists with calcium carbonate; both contribute to rock diagenesis. In the pores, biological activity promotes a complex cycling of calcium leading to recementation of the matrix and further lithification. Thus, this kind of calcrete is due to geological evolution as much as to biochemical control.     

Circadian Rhythms in Heart Rate,Motility, and Body Temperature of Wild‐type C57 and eNOS Knock‐out Mice Under Light‐dark,Free‐run,and After Time Zone Transition

The nitric oxide (NO) system is involved in the regulation of the cardiovascular system in controlling central and peripheral vascular tone and cardiac functions. It was the aim of this study to investigate in wild‐type C57BL/6 and endothelial nitric oxide synthase (eNOS) knock‐out mice (eNOS‐/‐) the contribution of NO on the circadian rhythms in heart rate (HR), motility (motor activity [MA]), and body temperature (BT) under various environmental conditions. Experiments were performed in 12∶12 h of a light:dark cycle (LD), under free‐run in total darkness (DD), and after a phase delay shift of the LD cycle by ?6 h (i.e., under simulation of a westward time zone transition). All parameters were monitored by radiotelemetry in freely moving mice. In LD, no significant differences in the rhythms of HR and MA were observed between the two strains of mice. BT, however, was significantly lower during the light phase in eNOS‐/‐ mice, resulting in a significantly greater amplitude. The period of the free‐running rhythm in DD was slightly shorter for all variables, though not significant. In general, rhythmicity was greater in eNOS‐/‐ than in C57 mice both in LD and DD. After a delay shift of the LD cycle, HR and BT were resynchronized to the new LD schedule within 5–6 days, and resynchronization of MA occurred within 2–3 days. The results in telemetrically instrumented mice show that complete knock‐out of the endothelial NO system—though expressed in the suprachiasmatic nuclei and in peripheral tissues—did not affect the circadian organization of heart rate and motility. The circadian regulation of the body temperature was slightly affected in eNOS‐/‐ mice.     

Photoanalogues of the Initiation Substrates of the RNA Polymerase II, 5‐Azido‐2‐Nitrobenzoyl Derivatives of the ATP γ‐Amidophosphate: The Possible Photoinduced Degradation of the Functional Group to an N‐Arylhydroxylamine

Photoanlogues of the initiation substrates of the RNA polymerase II, N₃Ar‐ NH(CH₂)_nNHpppA where N₃Ar is 5‐azido‐2‐nitrobenzoyl group (n = 2 or 4) were synthesized, allowing the preparation of photoreactive oligonucleotides in situ by RNA polymerase II for application as photolabels. Photolysis of p‐nitro‐substituted aromatic azide in aqueous medium was investigated. Using the azoxy‐coupling reaction it was possible to determine whether a nitrene or p‐nitrophenyl hydroxylamine azoxy compound is the trappable intermediate that is generated at ambient temperature in aqueous solution.     

Origin, functions and chemistry of H‐2 regulated odorants

Genes located within the major histocompatibility complex (MHC) of mice are responsible for individual differences in body odor (odortypes). In this review we suggest that the MHC genes themselves are responsible for odor differences among MHC‐congenic mice. Recent studies indicating that volatile carboxylic acids are at least in part responsible for the individual odors and what this finding implies about the pathway from gene to odorant are also reviewed. We suggest that odorants or their precursors are bound directly by MHC products and are released into serum and concentrated in urine. Finally, possible functions of MHC odortypes in mice are enumerated and important future research questions are raised. This revised version was published online in July 2006 with corrections to the Cover Date.     

Bioremediation of a petroleum‐contaminated cryic soil: Effects of phosphorus,nitrogen, and temperature

Bioremediation has been shown to be an effective means of treating petroleum‐contaminated soils in cold areas, although the conditions required to maximize bioremediation in cold region (cryic) soils are not well documented. A laboratory study was conducted to investigate the effects of nitrogen and phosphorus levels and temperature on petroleum bioremediation. A cryic entisol contaminated with diesel fuel was treated with nitrogen (0, 400, 800, or 1200 mg/kg of soil) and phosphorus (0, 60, 120, or 180 mg/kg of soil) and incubated at two temperatures (10 and 20°C). At 10°C, bioremediation rates were not affected by fertility treatments. At 20°C, reaction rates were increased by the addition of P, but unaffected by N. Regardless of fertility regime, the rate of diesel loss was much greater in soil incubated at 20°C than in soil incubated at 10°C.     

Synthesis of (−)‐DAPD

A new synthesis of (?)‐DAPD, suitable for large scale development, is described.     

Taphonomy of modern deep,cold‐temperate water coral reefs

Deep‐water corals are widely distributed along the cold‐temperate northeastern Atlantic continental margin. Despite the widespread occurrence of these aphotic coral constructions in deep shelf settings, the processes of framework formation and postmortem alterations which result in different preservational styles are still poorly known. Detailed mapping surveys on probably one of the largest Lophelia reef structures were carried out on the Sula Ridge, Mid‐Norwegian Shelf in 270 to 300 m depth. Side scan sonar records and camera surveys yield information at various scales of resolution on the reef complex which is more than 9 km long and up to 45 m high. Living Lophelia colonies effectively prevent colonization by other organisms and are successful in the rejection of passing detrital material from the soft tissue. In a healthy condition the coral is able to encrust repetitively attached organisms by selectively secreted sclerenchyme layers, thus, this defensive reaction results in the thickening of the skeleton. Early postmortem alteration in Lophelia colonies is introduced by the formation of a biofilm and Dodgella (fungi) infestation. The biofilm is associated with selective Fe‐Mn precipitation on the coral skeleton. This is the zone of intense attachment of sessile invertebrates such as serpulids, brachiopods, foraminifers and encrusting bryozoans. More advanced taphonomic stages show an increasing dominance in sponges which reduce the interskeletal framework porosity significantly. In addition, boring sponges excavate the thickly calcified Lophelia skeletons, thus leading to in situ collapsing structures on the sea floor. It is the intensity of sediment trapping biofilms and sponge colonization and the amount of imported detrital particles predominantly from the pelagial zone that control the generation of a pure coral rubble facies or the preservation of collapsed but mud‐rich detrital mounds.     

Building‐Site Camps and Extended Work Hours: A Two‐Week Monitoring of Self‐Reported Physical Exertion,Fatigue, and Daytime Sleepiness

Large‐scale construction work often requires people to work longer daily hours and more than the ordinary five days in a row. In order to minimize transportation times and optimize the use of personnel, workers are sometimes asked to live in temporary building‐site camps in the proximity of the work site. However, little is known about the biological and psychological effects of this experience. The objective of the present study was to investigate whether exposure to long work hours and extended workweeks while living in building‐site camps in between work shifts was associated with a build‐up of increased complaints of poor sleep, daytime sleepiness, physical exertion, and fatigue across a two‐week work cycle. Two groups of construction workers were examined. The camp group of 13 participants (mean age: 42±11 S.D. yrs) lived in building‐site camps and worked extended hours (between 07:00 and 18:00 h) and extended workweeks (six days in a row, one day off, five days in a row, nine days off). The home group of 16 participants (mean age 40±9 yrs) worked ordinary hours between 07:00 and 15:00 h and returned home after each workday. Self‐ratings of daytime sleepiness (Karolinska Sleepiness Scale), physical exertion (Borg CR‐10), and mood were obtained six or seven times daily during two workweeks. Fatigue ratings were obtained once daily in the evening, and ratings of sleep disturbances were obtained once daily in the morning with the Karolinska Sleep Diary. Data were evaluated in a repeated measures design. The results showed that both groups reported a similar level of daytime sleepiness, physical exertion, and mood across workdays and time points within a workday (all three‐way interactions had p>0.898). Although the home group reported earlier wake‐up times, the pattern of sleep disturbance ratings across the workdays did not differ between the groups. Both groups reported few sleep disturbances and good mood. However, the camp group reported higher physical exertion already at the start of work and showed a more gentle increase in ratings during the work shift and a smaller decline between the end of work and bedtime. The camp group also reported higher fatigue scores than the home group. However, none of the groups showed signs of increasing ratings in the progress of the two workweeks. For both groups, the ratings of daytime sleepiness formed a U‐shaped pattern, with the highest scores at awakening and at bedtime. Yet, the camp group reported higher daytime sleepiness than the home group at lunch break and at the second break in the afternoon. In conclusion, there were no signs of fatigue build‐up or accumulation of daytime sleepiness, physical exertion, or sleep disturbances in either group. Despite the fact that the camp group showed some signs of having trouble in recuperating in between work shifts, as indicated by the higher physical exertion ratings at the start of work, higher fatigue scores, and higher daytime sleepiness, the results constitute no real foundation for altering the camp group's current work schedule and living arrangements.     

Synthesis, 18F‐Radiolabelling and Biological Evaluations of C‐6 Alkylated Pyrimidine Nucleoside Analogues

Synthesis of pyrimidine derivatives with a side‐chain attached to the C‐6 of pyrimidine ring (6–14) is reported. Target compounds 8 and 12 were subjected to in vitro phosphorylation tests, determination of their binding affinities to herpes simplex virus (HSV‐1) thymidine kinase (TK) and catalytic turnover constants. Fluorinated pyrimidine derivative 12 (40 µM) exhibited better binding affinity for HSV‐1 TK than acyclovir (ACV, 170 µM) and ganciclovir (GCV, 48 µM). Catalytic turnover constant (k _cat) of 12 (0.08 s^? 1) was close to the k _cat values of ACV (0.10 s^? 1) and GCV (0.10 s^? 1). Furthermore, compounds 8 and 12 showed no cytotoxic effects in HSV‐1 TK‐transduced and non‐transduced cell lines. Besides, compounds 8 and 12 did not exhibit antiviral or cytostatic activities against several viruses and malignant tumor cell lines that were evaluated. The new fluorinated pyrimidine derivative 16 that is phosphorylated by HSV‐1 TK could be developed as non‐toxic PET‐tracer molecule. Thus, ¹⁸F labelling of the precursor 14 was performed by nucleophilic substitution using [¹⁸F] tetrabutylammonium fluoride as the fluorinating reagent.     

Alterations of the Characteristics of the Circadian Rest‐Activity Rhythm of Cancer In‐Patients

The aim of the present study was to evaluate the characteristics of the circadian rest‐activity rhythm of cancer patients. Thirty‐one in‐patients, consisting of 19 males and 12 females, were randomly selected from the Regional Cancer Center, Pandit Jawaharlal Nehru Medical College, Raipur, India. The rest‐activity rhythm was studied non‐invasively by wrist actigraphy, and compared with 35 age‐matched apparently healthy subjects (22 males and 13 females). All subjects wore an Actiwatch (AW64, Mini Mitter Co. Inc., USA) for at least 4–7 consecutive days. Fifteen‐second epoch length was selected for gathering actigraphy data. In addition, several sleep parameters, such as time in bed, assumed sleep, actual sleep time, actual wake time, sleep efficiency, sleep latency, sleep bouts, wake bouts, and fragmentation index, were also recorded. Data were analyzed using several statistical techniques, such as cosinor rhythmometry, spectral analysis, ANOVA, Duncan's multiple‐range test, and t‐test. Dichotomy index (I<O) and autocorrelation coefficient (r24) were also computed. The results validated a statistically significant circadian rhythm in rest‐activity with a prominent period of 24 h for most cancer patients and control subjects. Results of this study further revealed that cancer patients do experience a drastic alteration in the circadian rest‐activity rhythm parameters. Both the dichotomy index and r24 declined in the group of cancer patients. The occurrence of the peak (acrophase, Ø) of the rest‐activity rhythm was earlier (p<0.001) in cancer patients than age‐ and gender‐matched control subjects. Results of sleep parameters revealed that cancer patients spent longer time in bed, had longer assumed and actual sleep durations, and a greater number of sleep and wake bouts compared to control subjects. Further, nap frequency, total nap duration, average nap, and total nap duration per 1 h awake span were statistically significantly higher in cancer patients than control subjects. In conclusion, the results of the present study document the disruption of the circadian rhythm in rest‐activity of cancer in‐patients, with a dampening of amplitude, lowering of mean level of activity, and phase advancement. These alterations of the circadian rhythm characteristics could be attributed to disease, irrespective of variability due to gender, sites of cancer, and timings of therapies. These results might help in designing patient‐specific chronotherapeutic protocols.     

Origin of pre‐islamic architecture in West‐Africa

’Cultural theory’, launched by social anthropologist Mary Douglas, has been highly influential in the inter‐disciplinary field concerned with the study of risk perception and risk communication. The theory derives from the grid‐group analyses that Douglas developed in the 1970s. Cultural theory aims to explain universal ‘cultural bias’ by way of a general typology of group formation and a concomitant cosmology or world view. This article critically examines cultural theory and the study of hazards as culturally construed phenomena.     

Fitness of wild‐caught Drosophila melanogaster females: allozyme variants of GPDH, ADH, PGM, and EST

We have collected several hundred Drosophila melanogaster flies (near Davis, California), isolated them individually, without anesthesia, at the collecting site, and estimated the fitness components of the wild‐caught females under different environmental conditions. The fitness parameters measured are fecundity, oviposition rate, and productivity (egg‐to‐adult viability, development rate, and number of progeny). The environmental variables are two temperatures (22°C and 28°C) and two densities (‘scant’ and ‘crowded’). After the fitness measurements are completed for each individual female, its genotype is determined at four loci encoding enzymes: GPDH and ADH, located on chromosome II and PGM and EST‐C, located on chromosome III. Density has a large significant effect on productivity; temperature has significant effects on fecundity, oviposition rate, and development rate. The experiments show that allozyme polymorphisms are associated with selection effects. Fitness differences between allozyme genotypes occur for all fitness components, except oviposition rate. But which genotype is superior depends on the environmental conditions; heterozygotes exhibit higher fitness than homozygotes in a number of cases, but inferior in others. A unique feature of the present experiments is that the experimental flies are wild‐caught females rather than laboratory‐bred individuals. This revised version was published online in July 2006 with corrections to the Cover Date.