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5-HT-1a and 5-HT-1b selectivity of two phenylpiperazine derivatives: evidence for 5-HT-1b heterogeneity 总被引:4,自引:0,他引:4
The ability of m-trifluoromethylphenylpiperazine (TFMPP) and an N-substituted derivative, LY 165163 (p-NH2-PE-TFMPP), to discriminate 5-HT-1 binding sites labelled by [3H]5-HT is compared in rat corpus striatum and rat cortex. TFMPP displays at least a 30 fold selectivity for the 5-HT-1b subtype. Furthermore, TFMPP reveals heterogeneity within the 5-HT-1b binding sites. TFMPP displays a Kd of 6 nM for approximately two-thirds of the 5-HT-1b binding sites and a Kd of 273 nM for the remaining one third of the 5-HT-1b sites. p-NH2-PE-TFMPP, on the other hand, discriminates the 5-HT-1 sites in a manner similar to spiperone, displaying a 110 fold selectivity for the 5-HT-1a sites. p-NH2-PE-TFMPP displays a Kd of about 3 nM for the 5-HT-1a sites. p-NH2-PE-TFMPP does not discriminate subtypes within the 5-HT-1b binding sites. The significance of the selectivity of these two compounds as well as structurally related compounds is discussed. 相似文献
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By selective breeding, two sublines of rats with high or low activity of platelet serotonin (5HT) transporter (5HTt) have been developed (Wistar-Zagreb 5HT rats). Previous studies demonstrated significant differences between the sublines in the expression of platelet 5HTt at the level of both, mRNA and protein. Pharmacological studies showed marked alterations in brain 5HTt function, indicating differences in central serotonin homeostasis, although analysis of regional brain 5HTt gene expression did not show analogous differences. In this study, we searched for possible changes in the expression of the two central 5HT receptor subtypes: 5HT-1A and 5HT-1B, both participating in the regulation of brain 5HT transmission. Semi-quantitative RT-PCR, with three different housekeeping genes as internal standards, showed no differences in the levels of 5HT-receptor expression between the sublines. Results suggest that constitutional alteration of 5HT homeostasis, induced by selective breeding for the extremes of platelet 5HTt activity, did not cause measurable changes in the expression of central 5HT-1A (hippocampus) and 5HT-1B (striatum) receptors in the mentioned rat sublines under physiological conditions. 相似文献
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一种新发现的流感病毒—H5N1 总被引:4,自引:0,他引:4
1997年 5月 ,香港首次分离到一种新的A型流感病毒———H5N1[1,2 ] ,至该年底共有 18位患者确诊被H5N1感染 ,其中 6人死亡[3 ,4 ] 。这是对人类具强毒性的流感病毒新亚型首次被确定。在呼吸系统疾病的病毒中 ,流感病毒因其有抗原性变异而不同于其它病毒 ,特别是它的表面抗原如血凝素 (hemagglutinin ,HA)和神经氨酸酶 (neu raminidase ,NA)。主要有两种类型变异 :抗原性漂离(因编码基因点突变的累积导致少量氨基酸改变 )和抗原性转移 (由于不同A型流感病毒亚型的抗原基因的重配引起表面抗原分子广泛的… 相似文献
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1. 5-Phosphoribosyl 1-methylenediphosphonate was isolated after reaction of ribose 5-phosphate and O-adenylyl methylenediphosphonate with 5-phosphoribosyl pyrophosphate synthetase from Ehrlich ascites-tumour cells. 2. The analogue reacted with adenine phosphoribosyltransferase, hypoxanthine phosphoribosyltransferase and nicotinamide phosphoribosyltransferase [K(m) (analogue)/K(m) (5-phosphoribosyl pyrophosphate) 0.17, 0.19 and 6.3 respectively; V(max.) (analogue)/V(max.) (5-phosphoribosyl pyrophosphate) 0.011, 0.26 and 1.1 respectively]. 3. The analogue was not a substrate for 5-phosphoribosyl pyrophosphate amidotransferase or orotate phosphoribosyltransferase. 4. Ribose 5-phosphorothioate was synthesized by allowing ribose to react with thiophosphoryl chloride in triethyl phosphate. The analogue was a substrate for 5-phosphoribosyl pyrophosphate synthetase from Ehrlich ascites-tumour cells. When this reaction was coupled to either adenine phosphoribosyltransferase or hypoxanthine phosphoribosyltransferase, adenosine 5'-phosphorothioate or inosine 5'-phosphorothioate was formed respectively. 相似文献
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[3H]5-HT binding sites were analyzed in membranes prepared from the rabbit caudate nucleus (CN). [3H]5-HT labeled both 5-HT1A and 5-HT1C recognition sites, defined by nanomolar affinity for 8-OH-DPAT and mesulergine respectively; however, these represented only a fraction of total specific [3H]5-HT binding. Saturation experiments of [3H]5-HT binding in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine to block 5-HT1A and 5-HT1C sites revealed that non-5-HT1A/non-5-HT1C sites represented about 60% of the total 5-HT1 sites and that they exhibited saturable, high affinity, and homogeneous binding. The pharmacological profile of the non-5-HT1A/non-5-HT1C sites (designated 5-HT1R) also differed from that of 5-HT1B and 5-HT2 sites, but was similar to that of the 5-HT1D site. However, significant differences existed between the 5-HT1D and 5-HT1R sites for their Ki values for spiperone, spirilene (an analog of spiperone), metergoline, and methiothepin. The study of modulatory agents (calcium and GTP) also showed differences between the 5-HT1R and 5-HT1D sites. For example, the effects of GTP on agonist binding to the 5-HT1R sites were less than on the 5-HT1D sites in bovine caudate. In addition, calcium enhanced the effects of GTP on the 5-HT1R sites, whereas calcium inhibited the GTP effect on the 5-HT1D sites. The present findings demonstrate the presence of a high-affinity [3H]5-HT binding site in rabbit CN, designated 5-HT1R, that is different from previously defined 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 sites. 相似文献
9.
Zou X Ji C Jin F Liu J Wu M Zheng H Wang Y Li X Xu J Gu S Xie Y Mao Y 《Genes & genetic systems》2004,79(3):177-182
Two novel splice variants of CDK5RAP1, named CDK5RAP1_v3 and CDK5RAP1_v4, were isolated through the large-scale sequencing analysis of a human fetal brain cDNA library. The CDK5RAP1_v3 and CDK5RAP1_v4 cDNAs are 1923bp and 1792bp in length, respectively. Sequence analysis revealed that CDK5RAP1_v4 lacked 1 exon, which was present in CDK5RAP1_v3, with the result that these cDNAs encoded different putative proteins. The deduced proteins were 574 amino acids (designated as CDK5RAP1_v3) and 426 amino acids (CDK5RAP1_v4) in length, and shared the 420 N-terminal amino acids. RT-PCR analysis showed that human CDK5RAP1_v3 was widely expressed in human tissues. The expression level of CDK5RAP1_v3 was relatively high in placenta and lung, whereas low levels of expression were detected in heart, brain, liver, skeletal muscle, pancreas, spleen, thymus, small intestine and peripheral blood leukocytes. In contrast, human CDK5RAP1_v4 was mainly expressed in brain, placenta and testis. 相似文献
10.
1. Methylation and thiation of 5-fluorouracil led to 1,3-dimethyl-5-fluoro-4-thiouracil, the amination of which was examined under various conditions. At high dilution, and in the presence of a large excess of NH3, 1,3-dimethyl-5-fluoro-4-thiouracil was converted to 1,3-dimethyl-5-fluorocytosine in 60% yield. 2. Two procedures were employed for methylation of 5-fluoro-1-methylcytosine and 5-fluorocytidine. Treatment of each of these with diazomethane in alcohol-ether gave a complex mixture of products, the major one of which was the desired 3-methyl derivative. By contrast, treatment with methyl iodide in dimethylsulphoxide led exclusively to the 3-methyl derivatives in much better yeilds. 3. Ultraviolet absorption spectra and pKa values are presented for 1-substituted N-methyl-5-fluoro- and 5-bromo-cytosines. The basicity method was applied to determine the tautomeric equilibrium constants of the 1-substituted 5-halogenocytosines. The results show that the proportion of the imino forms of these compounds is of the same order of magnitude as for 1-substituted cytosines, and hence is unlikely to account for the observed mutagenic effects of 1-substituted 5-halogenocytosines. 相似文献
11.
The evolutionary dynamics of the H5N1 virus present a challenge for conventional control
measures. Efforts must consider the regional aspects of endemic H5N1.The H5N1 virus has spread across Asia, Europe and Africa, and has infected birds in several
endemic areas, including China, Indonesia, Vietnam and Egypt. H5N1 outbreaks pose a massive
threat for the poultry industry and, ultimately, for human health [1]. However, the rapid spread of the virus also offers the opportunity to
study and learn from its dynamics in the wild. The insights gained should inform new public
health policies and preventive actions against a possible pandemic.Progress in influenza research has been impressive. In particular, the application of reverse
genetics has led to the identification of mutations and reassortment changes that determine
virus virulence. Perhaps the most significant results come from the two now infamous studies,
published in Nature and Science, about the generation of recombinant H5N1
viruses that are transmissible in ferrets [2,3]. These advances show that we are steadily elucidating influenza
virus at the molecular level. By contrast, our understanding of the dynamics of highly
pathogenic influenza virus in the environment remains limited [4,5].Highly pathogenic avian influenza (HPAI) is an important poultry disease. The major reservoir
of the virus is wild waterfowl, and infected birds are usually asymptomatic as a result of
long-term evolutionary adaptation [1,6]. After transmission from wild waterfowl to poultry, however, avian
influenza viruses occasionally become highly pathogenic and can cause mortalities of up to
100% within 48 h of infection. The standard method for controlling an HPAI outbreak is the
testing and culling of all infected poultry, and the setting up of a concentric control area
around the infected flock.The HPAI H5N1 virus, circulating in Eurasia and Africa, emerged in China around 1997
[1] but it only infected terrestrial birds at the
time. Continuous transmission in poultry eventually allowed the virus to evolve, resulting in
large outbreaks in China in 2005 with high mortality in wild waterfowl. The virus spread
rapidly, probably though migratory birds, to Central Asia, Europe, the Middle East and Africa.
Such ‘east to west'' movements of H5N1 viruses over comparably long distances have
not since been recorded. Moreover, migrating wildfowl have begun to spread the virus
intermittently between Asia and Siberia [7]. This H5N1
lineage is the longest-circulating HPAI virus that has been reported, and it has reached
epizootic levels in both domestic and wild bird populations.…the challenge is to understand the evolution of H5N1 to better
predict new strains that could become a serious threat for human healthOne of the striking characteristics of the H5N1 lineage, in contrast with other HPAI, is its
infectivity toward mammals. H5N1 can be directly transmitted from birds to humans and cause
severe disease, although it has a significantly lower transmissibility than seasonal influenza
viruses [1]. So far, 608 cases of human H5N1 infections
have been reported with 59% mortality [5]. Most human
infections have resulted from close contact with H5N1-infected poultry or poultry products,
and no sustained human–human transmission has as yet been documented. Nonetheless, a
potential H5N1 pandemic remains a great concern for public health.The viruses that caused the five influenza pandemics since 1900 arose by two mechanisms:
reassortment among avian, human and swine influenza viruses, and accumulation of mutations in
an avian influenza virus [1,8]. Triple reassortment between avian H5N1, swine H3N1 and H1N1 viruses, and
double reassortment between avian H5N1 and H9N2 viruses has already been reported in Asia,
which raises concerns about new reassortment viruses that could infect humans [9,10]. Meanwhile, research has
identified some 80 genetic mutations that could increase infectivity of avian influenza
viruses in mammals, and thus potentially facilitate avian influenza evolution to generate a
pandemic strain [8,11].
H5N1 strains with some of these mutations have often been found in bird populations
[5] and in human H5N1 strains [12]. Indeed, specific mutations that could confer switching in
receptor-binding specificity were reported in H5N1-infected patients in Thailand
[13]. The two controversial studies published in
Nature and Science also showed how a handful of mutations might enable the
H5N1 virus to be transmitted between humans [2,3]. Pathogenic variants of the H5N1 virus with a higher pandemic
potential could naturally evolve; the challenge is to understand the evolution of H5N1 to
better predict new strains that could become a serious threat for human health.…continuous replication of H5N1 virus in Egypt has provided a
valuable opportunity to study the impact of genetic evolution on phenotypic variation
without reassortmentThe evolutionary dynamics of the Egyptian H5N1 strains provide clues to understanding the
pandemic potential of H5N1. The virus was introduced only once in Egypt, in early 2006, and
spread among a variety of bird species, including chickens, ducks, turkeys, geese and quail
[14]. The virus rapidly evolved to form a
phylogenetically distinct clade that has since diverged into multiple sublineages
[15]. Thus, continuous replication of H5N1 virus in
Egypt has provided a valuable opportunity to study the impact of genetic evolution on
phenotypic variation without reassortment.After diversification in local bird populations, some new H5 sublineages have emerged in
Egypt with a higher affinity for human-type receptors. Indeed, since their emergence in 2008,
almost all human H5N1 strains in Egypt have been phylogenetically grouped into these new
sublineages, which can be transmitted to humans with a higher efficacy than other avian
influenza viruses. This might explain why, since 2009, Egypt has had the highest number of
human cases of H5N1 infection, with more than 50% of the cases worldwide [5]. Fortunately, these Egyptian H5N1 sublineages still do not have
binding affinity for receptors in the upper respiratory tract and, therefore, do not sustain
transmission in humans. However, it increases the risk of H5N1 variants that are better
adapted to humans after viral replication in infected patients.…Egypt is regarded as the country with the highest H5N1 pandemic
potential worldwideThe Egyptian H5N1 sublineages are also diversifying antigenically in the field, as some are
no longer crossreactive to other co-circulating sublineages [15]. Moreover, faint traces of species-specific evolutionary changes have
been detected [16], implying a change in their host
species. It shows that the H5N1 virus has undergone significant diversification in Egypt
during the past seven years. Of greater concern, however, are Egyptian H5N1 strains that carry
mammalian influenza virus type PB2 and have lost the N-linked 158 glycosylation site in the
top region of haemagglutinin [15,17], both of which can potentially facilitate viral transmission to humans.
The genetic diversification of H5N1 virus in Egypt represents an increasing pandemic
potential, and Egypt is regarded as the country with the highest H5N1 pandemic potential
worldwide [18].A similar situation exists in other geographical areas. Multiple clades and sublineages of
H5N1 are co-circulating in Asia, occasionally enabling reassortment events within and beyond
the viral subtypes in the field [19,20]. Several H5N1 strains with enhanced binding affinity to human-type
receptors have been reported in Indonesia [12].
Similarly, avian and swine H5N1 strains with an altered receptor-binding preference have been
isolated sporadically in Indonesia and Laos [21,22]. As in other areas, distinct groups of H5N1 viruses are
circulating amongst themselves and with other avian influenza viruses, generating diverse
viral phenotypes in nature. The evolutionary dynamics of H5N1 might even accelerate in the
wild. H5N1 viruses diverge genetically in ducks [23];
they can transfer the virus over long distances by migration. Thus, the H5N1 virus has
established a complex life cycle in nature with accelerated evolutionary dynamics. The
pandemic threat of H5N1 remains a serious concern and might be increasing.Control measures based on isolating and culling are still the gold standard for controlling
the early phase of an H5N1 outbreak, and worked against the H5N1 outbreaks in Hong Kong in
1997 and in Thailand in 2004 [4]. However, this measure
failed in several countries and made H5N1 endemic. Cross-border circulation of H5N1 further
complicates implementation of a classical control strategy based on culling in the infected
area.In response, public health officials in several countries, including Egypt and Indonesia,
advocate poultry vaccination as a preventive or adjunct control measure [1]. Although vaccination does not completely prevent infections, its
proper use can help to control avian influenza outbreaks by reducing virus transmission from
infected animals. However, it can also increase vaccine-driven evolution among avian influenza
viruses. The endemic status of H5N1, which can cause devastating local epidemics, puts
pressure on health officers to use a vaccine or a vaccination strategy that might eventually
increase selective pressure and thereby accelerate H5N1 evolution. Given the high mutability
and diversity of circulating viruses, it seems best to avoid using a vaccine based on a strain
from a different geographical area because there would only be a partial antigen match; such a
heterologous vaccine would only be effective in the short term compared with a homologous
vaccine. During past control of H5N1 epidemics using imported vaccines, escape mutants have
emerged within about a year of the start of vaccination, which made the epidemic even worse
[14]. When a vaccination strategy is implemented in
an endemic area, the vaccine seed strain should be selected from the same geographical area to
try to get the longest possible protection. Vaccine seed virus selection must be periodically
revised to produce well-matched and efficacious vaccines.Close communication and workshops hold the greatest potential for
controlling the H5N1 virusIn most cases, H5 vaccine for an endemic area comes from a foreign supplier. It would be
necessary to enable foreign manufacturers to produce customized H5 vaccines based on epidemic
strains from different areas. The best approach might be a plasmid-based reverse genetics
system to construct vaccine seed viruses [1]. In
egg-based production, which is the basis of flu vaccine production, the seed virus needs to be
adapted for high growth. This time-consuming step carries the risk of antigenic changes during
vaccine production. Yet, advances in influenza reverse genetics have led to the development of
cell culture systems to produce recombinant viruses, which would enable rapid genetic
mutagenesis and reassortment. Once reverse genetics generates a virus genome that is well
adapted to growth in cell culture, the haemagglutinin and neuraminidase genes can be easily
interchanged with those of other influenza viruses. In addition, virus growth in cell culture
can shorten production time, which increases the probability of selecting a seed virus
antigenically appropriate for the upcoming flu season, and enables a rapid increase in
production if necessary [24].A control strategy imposed without consideration of regional customs will
not be successfulGiven the zoonotic risks of influenza viruses to both humans and animals, the establishment
of a vaccine production system applicable to both human and animal infections is an urgent
issue. The capacity of vaccine production needs to be flexible for seasonal, pre-pandemic and
pandemic vaccines. Advances in genetic engineering facilitate in vitro control of
human- and avian-type receptor expression on cultured cells, which should allow both human and
avian influenza viruses to grow in the same system. As vaccine production capacity based on
cell culture develops, commercial production of H5N1 vaccines tailored to each geographical
area should become possible. In addition, emergency vaccination guidelines, such as
pre-pandemic vaccine stockpiling, expanding and accelerating vaccine production and setting
vaccination priorities, should be formulated in a business–government partnership, to
ensure pandemic preparation. There is no guarantee that the H5N1 virus will be the next
pandemic influenza strain. However, exploring options for versatile vaccine manufacturing is a
key to controlling zoonotic influenza viruses, including H5N1.The complexity of H5N1 ecology also makes control of endemic H5N1 by vaccination a complex
task. The problem is that antigenically different groups of viruses, which are not
crossreactive, are often co-circulating in endemic areas. Circulation of viruses in each
sublineage is not restricted in terms of geography or host species, which complicates efforts
to use a vaccine produced against antigens from a single virus strain [15]. Of greater concern, H5N1 virus infects a variety of bird species
[1], which means the vaccination targets have
expanded. Bird species differ in their optimal vaccination protocol—for example, the
single vaccination used routinely in chickens does not induce an adequate immune response in
turkeys, which require multi-dose vaccination at an older age [25]. Furthermore, rearing many bird species and their hybrid breeds in
uncontrolled confinement is common in H5N1 endemic countries, especially in rural areas.
Therefore, the immunogenicity of existing vaccines is probably inadequate to protect all
target species with a single vaccination scheme. Endemic H5N1 already forces public health
officials to redefine vaccine development policy to improve both vaccine immunogenicity and
vaccination regime.Unfortunately, it is unlikely that science will ever produce a clear
answer as to when, where and how the next pandemic influenza virus will emergeToday, there are numerous techniques that could overcome these problems by increasing
immunogenic potency and crossreactivity. Innovative vaccine formats—multivalent,
universal, nasal and synthetic vaccines—possibly coupled with the use of adjuvants,
could improve the global vaccine supply [24]. These new
technologies should be applied as soon as possible. Nevertheless, no single technique can
probably resolve the underlying complexity of H5N1 dynamics. Over-reliance on vaccination
might therefore only worsen the situation. Vaccination can help control endemic H5N1 only when
administered as part of an integrated control programme that includes surveillance, culling,
restricting host movement and enhanced quarantine and biosecurity.The complex evolutionary dynamics of the H5N1 virus are challenging host species barriers and
the ecology brings H5N1 into close proximity to humans [1]. The close link between the virus and humans is a multifaceted phenomenon
that can affect health in myriad ways. Thus, we need to redefine control strategies to address
the nature of H5N1 dynamics. Surveillance is the basis of infection control in the field. Wild
birds and their predators should be included as surveillance targets, thereby expanding the
H5N1 host species range. Another drawback is the fact that epidemiological studies focus
mainly on virus genotyping. Although genetic data is informative, the diversity of H5N1
viruses makes characterization based only on genetic traits difficult. Characterization of
viral phenotypes—antigenicity, receptor-binding preference, pathogenicity and
transmissibility—is equally important for investigating the evolutionary dynamics of
H5N1 viruses in nature. We would need techniques to determine easily viral phenotype, in
particular new rapid diagnostic systems that can be used for timely epidemiological
investigations and rapid infection control measures [1].
For example, portable kits that can determine virus receptor specificity would allow field
testing of whether a particular avian influenza virus strain has adapted to human-type
receptors, thereby adding a new dimension for characterizing and assessing H5N1
outbreaks.Our perception of H5N1 control should change from short-term hunting to
long-term controlThe large-scale slaughter of all known and suspected infected birds in H5N1 endemic countries
is hugely expensive in terms of execution costs and compensation for lost poultry. Financial
assistance from international organizations might be needed to promote the thorough
implementation of such a policy. However, H5N1 endemic countries are not all poor nations and
some have already built a certain level of technology infrastructure. Thus, transfer of
epidemiological skills and concepts to local health officers and scientists is a priority.
Overseas collaborations between technologically developed countries and their institutions,
and H5N1 endemic countries and their institutions, should be established at a functional
level. Close communication and workshops hold the greatest potential for controlling the H5N1
virus. Such projects supported by governments and funding agencies would encourage
establishment of bilateral and multilateral relationships between developed countries and the
developing countries, which are the epicentres of H5N1 outbreaks. Sharing information about
risk and risk management is one of the key methods for reducing the threat of future H5N1
epidemics.Globalization has had major benefits for international travel and trade, and sharing of
information. The improvements in information technology have dramatically increased the speed
and ease of data flow [26]. Intelligence networks
facilitate instantaneous sharing of information and enable global warnings about potential
hazards as well as problem-solving. Moreover, collaborative research centres, which have been
established on reciprocal bases between scientifically advanced countries and institutes and
overseas partner countries and institutes in Asia, Africa and Latin America, are important
players in information networking—for instance the Institute Pasteur Network, the
Mahidol Oxford Tropical Medicine Research Unit and Japan Initiative for Global Research
Network on Infectious Diseases. Linking such laboratory-based networks should be the next
step. This would have a profound synergistic effect by maximizing research capacity, human
resources and geographic coverage to build a robust global-scale network for infection
control.However, regional socio-cultural issues can be a significant concern for virus control
wherever accepted values and scientific understanding might differ. Multiple local and
regional factors—customs, religion, politics and economics—can affect H5N1 control
in an area. Successful implementation of an H5N1 control strategy depends largely on mutual
understanding and consideration of local idiosyncrasies.Some examples from Egypt show how regional identity can be closely linked with local public
health initiatives. Egypt is an Islamic nation and bird meat is an important source of animal
protein, and the only source in some rural areas [14].
A large proportion of Egyptian households in rural areas raise poultry. Although broiler and
layer chickens are raised under modern hygienic controls on commercial farms, backyard birds
are raised in open uncontrolled farms, leaving them free to interact with other birds (Fig 1A). The poultry meat trade depends mainly on live bird markets in
traditional bazaars (Fig 1B), because of a preference for freshly
slaughtered poultry. Pigeon towers are built on farms, backyards and roofs throughout villages
to raise pigeons for eating. Generally, birds in Egypt are raised in proximity to humans
(Fig 1C), which presents an increasing risk of human H5N1 infection in
Egypt and establishment of endemic H5N1 in birds nationwide.Open in a separate windowFigure 1Socio-cultural traditions in rearing birds for food in Egypt. (A) Free rearing
of backyard birds. (B) Live birds at a downtown market. (C) An example of
the intertwined relationship between birds and humans.Such regional identity is inseparable from socio-cultural contexts, making fundamental change
virtually impossible. Although there are many scenarios in which a local public health system
could be improved by food safety standards and veterinary inspection or short-term closing of
live bird markets for virus clearance, H5N1 control measures have to be implemented whilst
respecting the intrinsic socio-cultural traditions in the region. A control strategy imposed
without consideration of regional customs will not be successful. It is the local health
officers and scientists who are best suited to address the enormous complexity and breadth of
issues required for H5N1 control. They also experience H5N1 outbreaks in their area on a
regular basis and have a great incentive to be involved in infection control. Therefore, it is
important to include local expertise in planning and implementing a control
strategy.Science in an area such as infectious disease research can no longer be
viewed as independent of societal needs…Science is frequently looked at as if it can produce a ‘silver bullet'' to solve
every problem. Early success in vaccine and antibiotic development also created a false sense
of optimism that scientific methods could eliminate the risk of infection. However, the
reality has turned out to be different—some infectious diseases remain uncontrollable
and far from eradication. Given the mutable and diversifying nature of avian influenza
viruses, there is a significant possibility that different avian influenza subtypes and
strains do not follow a single evolutionary pathway. Unfortunately, it is unlikely that
science will ever produce a clear answer as to when, where and how the next pandemic influenza
virus will emerge. Our perception of H5N1 control should change from short-term hunting to
long-term control. The ecology of H5N1 virus brings it into close proximity to humans. The
most important strategy is to minimize contact between terrestrial poultry and wild waterfowl
to segregate H5N1 in poultry, because H5N1 spread would be uncontrollable if it established a
stable equilibrium in waterfowl. For example, H5N1 viruses in Siberia have not been
consistently isolated each year from carcasses and faeces of wildfowl migrating from Asia
[7]. This implies that H5N1 circulation in the wild
still largely depends on occasional introduction from poultry. It is possible that trials to
limit H5N1 infection in poultry would lead to a reduction in viral spread and a dwindling
evolutionary path in nature. Infection control policy must abandon fixed strategies in favour
of flexible ones to keep pace with the evolutionary dynamics of pathogens such as H5N1 (Fig 2).Open in a separate windowFigure 2Changing dynamics of H5N1 virus in the field. Endemic H5N1 virus diversifies in nature,
making traditional control measures extremely difficult.Today''s infection control strategy is becoming largely dependent on the reliability and
accuracy of information networking. However, the vast flood of scientific information can hide
erroneous information and easily mislead the public [26]. Of greater concern, globalization has prompted the centralization of
capital and resources, which can lead to an overemphasis on certain research topics. As a
consequence, research projects are often short term, without consideration of effects that
might have a long-term social impact [27]. This has led
to a debate about whether to limit publication of certain types of research or keep scientific
information completely accessible. There is probably no easy answer to this. Our global
society needs a more mature approach to support research projects that are accurate
reflections of societal needs in public health. At the same time, the increasing links between
science and society put more pressure on science to play a greater role in society. This is a
serious dilemma—how to use science to solve societal problems whilst maintaining its
autonomy [27]. Science in an area such as infectious
disease research can no longer be viewed as independent of societal needs; we need to
establish a balance between the pursuit of independent basic research and its application for
solving clinical problems and crises.?
Open in a separate windowYohei WatanabeOpen in a separate windowKazuyoshi IkutaOpen in a separate windowMadiha S Ibrahim 相似文献
12.
Cordycepin sensitive mutants of Saccharomyces cerevisiae, which are permeable to 5'-deoxy-5'-methylthioadenosine (MTA), were used to study the fate of the methylthioribose carbons of this purine nucleoside. Evidence is presented for the recycling of the methylthio group and part of the ribose portion of MTA in a biosynthetic pathway which leads to the synthesis of methionine. The main pathway involves the phosphorylytic cleavage of MTA by MTA phosphorylase yielding 5-methylthioribose 1-phosphate and adenine as products. Loss of the phosphate group of 5-methylthioribose 1-phosphate, concurrent with the rearrangement of the ribose carbons, leads to the synthesis of 2-keto-4-methylthiobutyric acid. In the final step of the sequence, 2-keto-4-methylthiobutyric acid is converted to methionine via transamination. Several compounds not directly associated with the biosynthesis of methionine were also isolated. These compounds, which may arise through the degradation of intermediates in the pathway, were: 5'-methylthioinosine, a deaminated catabolite of MTA; 5-methylthioribose, a result of the phosphorylysis of 5-methylthioribose 1-phosphate, and 3-methylthiopropionaldehyde, 3-methylthiopropionic acid and 2-hydroxy-4-methylthiobutyric acid, all arising from the catabolism of 2-keto-4-methylthiobutyric acid. 相似文献
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Surman MD Freeman EE Grabowski JF Hadden M Henderson AJ Jiang G Jiang XM Luche M Khmelnitsky Y Vickers S Viggers J Cheetham S Guzzo PR 《Bioorganic & medicinal chemistry letters》2010,20(23):7015-7019
A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy. 相似文献
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In an attempt to define pharmacophoric differences between 5-HT1, 5-HT1A and 5-HT2 recognition sites, a number of rigid analogs were studied and compared to analogous free chain tryptamines. Racemic partial ergolines RU 27849 and RU 28306 showed reduced potency at all 5-HT1 sites, but were at least equipotent to analogous tryptamines at the 5-HT2 site. A nonergoline-like constrained analog of tryptamine was similar in potency to RU 27849 at all 5-HT1 sites, but showed a 4-fold enhancement in potency over RU 27849 and tryptamine at the 5-HT2 site. At all 3 sites, 3-(tetrahydropyridyl) indoles (unless substituted at the indole 2-position) were the most potent rigid analogs studied and represent the most promising class for the development of selective compounds. 相似文献
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Nathan J. Cherrington J. Greg Falls Randy L. Rose Kieran M. Clements Richard M. Philpot Patricia E. Levi Ernest Hodgson 《Journal of biochemical and molecular toxicology》1998,12(4):205-212
Full-length cDNA clones encoding FMO1 and FMO5 have been isolated from a library constructed with mRNA from the liver of a female CD-1 mouse. The derived sequence of FMO1 contains 2310 bases: 1596 in the coding region, 301 in the 5′-flanking region, and 413 in the 3′-flanking region. The sequence for FMO5 consists of 3168 bases; 1599 in the coding region, 812 in the 5′-flanking region, and 757 in the 3′-flanking region. The sequence of FMO1 encodes a protein of 532 amino acids with a predicted molecular weight of 59.9 kDa and shows 83.3% identity to human FMO1 and 83–94% identity to other FMO1 homologs. FMO5 encodes a protein of 533 amino acids with a predicted molecular weight of 60.0 kDa and 84.1% identity to human FMO5 and 83–84% identity to other FMO5 orthologs. Two GxGxxG putative pyrophosphate binding domains exist beginning at positions 9 and 191 for FMO1, and 10 and 192 for FMO5. Mouse FMO1 and FMO5 were expressed in E. coli and show similar mobility to the native proteins as determined by SDS-PAGE. The expressed FMO1 protein showed activity toward methimazole, and FMO5 was active toward n -octylamine. In addition, FMO1 was shown to metabolize radiolabeled phorate, whereas FMO5 showed no activity toward phorate. © 1998 John Wiley & Sons, Inc. J Biochem Toxicol 12: 205–212, 1998 相似文献
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Various 5-substituted 1-beta-D-arabinofuranosyluracil 5'-triphosphates (H, methyl, ethyl, n-propyl, n-butyl, (E)-bromovinyl, styryl, and beta-phenylethyl derivatives) were prepared and their inhibitory effects on two different herpes virus-induced DNA polymerases (OMV and HCMV) were studied. These dTTP analogues inhibited the incorporation of [3H]dTMP into DNA in vitro. Among them, analogues having a vinyl group at the 5-position were strongly active against DNA polymerases induced on herpes virus infection. Kinetic analysis showed that the inhibition by the analogues was essentially competitive with respect to the substrate, dTTP. The K1 values (microM) for AraUTP (2.4), AraTTP (1.0), BVAUTP (0.8), and StUAUTP (0.8) were smaller than the Km value (microM) for dTTP (3.4), but those for AraEtUTP, AraPrUTP, and AraBuUTP (5-14) were larger than the Km for dTTP in the case of HCMV-induced DNA polymerase. In contrast to these results, OMV-induced DNA polymerase seemed to be more resistant to these inhibitors than HCMV-induced DNA polymerase. However, the mode of the structure of substituent groups at the 5-position of base moieties is almost the same for the two DNA polymerases, except for in the case of AraUTP itself. 相似文献