Infectious disease. Research (genomics) is crucial to attacking malaria

Solving the enormous problem of malaria worldwide will require a balance between investments in research and control. In this point-counterpoint, two scientists describe the rationales for these very different strategies. Steve Hoffman believes that genomics research is the best investment in the future if we have the vision of malaria eradication. Chris Curtis presents an opposing viewpoint, that low-tech control approaches are the practical ones under current conditions.     

Infectious disease. The case for deemphasizing genomics in malaria control

Solving the enormous problem of malaria worldwide will require a balance between investments in research and control. In this point-counterpoint, two scientists describe the rationales for these very different strategies. Steve Hoffman believes that genomics research is the best investment in the future if we have the vision of malaria eradication. Chris Curtis presents an opposing viewpoint, that low-tech control approaches are the practical ones under current conditions.     

Vaccines. Searching for a parasite's weak spot

Using a host of new technologies, vaccine developers are trying to target the malaria parasite at every stage of its complex life cycle. Researchers now predict that within 5 or 10 years they will have a successful vaccine that will actually save lives. But in malaria vaccine research, the concept of "success" comes with caveats.     

Plasmodium chloroquine resistance and the search for a replacement antimalarial drug

Genetic and biochemical research is providing new information on the mechanism of chloroquine resistance. Drug discovery initiatives are finding new leads that have favorable pharmaceutical properties and efficacy against chloroquine-resistant malaria.     

Dual infection with HIV and malaria fuels the spread of both diseases in sub-Saharan Africa

Mounting evidence has revealed pathological interactions between HIV and malaria in dually infected patients, but the public health implications of the interplay have remained unclear. A transient almost one-log elevation in HIV viral load occurs during febrile malaria episodes; in addition, susceptibility to malaria is enhanced in HIV-infected patients. A mathematical model applied to a setting in Kenya with an adult population of roughly 200,000 estimated that, since 1980, the disease interaction may have been responsible for 8,500 excess HIV infections and 980,000 excess malaria episodes. Co-infection might also have facilitated the geographic expansion of malaria in areas where HIV prevalence is high. Hence, transient and repeated increases in HIV viral load resulting from recurrent co-infection with malaria may be an important factor in promoting the spread of HIV in sub-Saharan Africa.     

Crystal structure of the malaria vaccine candidate apical membrane antigen 1

Apical membrane antigen 1 from Plasmodium is a leading malaria vaccine candidate. The protein is essential for host-cell invasion, but its molecular function is unknown. The crystal structure of the three domains comprising the ectoplasmic region of the antigen from P. vivax, solved at 1.8 angstrom resolution, shows that domains I and II belong to the PAN motif, which defines a superfamily of protein folds implicated in receptor binding. We also mapped the epitope of an invasion-inhibitory monoclonal antibody specific for the P. falciparum ortholog and modeled this to the structure. The location of the epitope and current knowledge on structure-function correlations for PAN domains together suggest a receptor-binding role during invasion in which domain II plays a critical part. These results are likely to aid vaccine and drug design.     

Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria

Tumor necrosis factor, or cachectin (TNF-alpha), a protein with a wide range of biological activities, is produced mainly by macrophages and may be important in inflammatory processes. The role of TNF-alpha in the pathogenesis of cerebral malaria was investigated in a murine model. Most CBA mice infected with Plasmodium berghei anka die between days 6 and 14 with acute neurological manifestations unrelated to the level of parasitemia, whereas mice of some other strains have malaria of the same severity that ends in death after 3 to 4 weeks without neurological manifestations. The activity of serum TNF-alpha was considerably increased in CBA/Ca mice with cerebral malaria but not in Plasmodium berghei-infected mice that did not develop this complication. One injection of rabbit antibody to TNF-alpha on day 4 or 7 fully protected infected mice from cerebral malaria without modifying the parasitemia, whereas immunoglobulins from normal rabbit had no effect. In mice with cerebral malaria, the cerebral vessels showed focal accumulations of packed macrophages often containing infected erythrocytes; this lesion was not seen in mice treated with antibody to TNF-alpha or in untreated mice without cerebral malaria. These findings indicate that TNF-alpha has an important role in the pathogenesis of cerebral malaria in this murine model and suggest that local accumulation and activation of macrophages may lead to the predominance of lesions in the central nervous system.     

Naturally acquired antibodies to sporozoites do not prevent malaria: vaccine development implications

The first human vaccines against the malaria parasite have been designed to elicit antibodies to the circumsporozoite protein of Plasmodium falciparum. However, it is not known whether any level of naturally acquired antibodies to the circumsporozoite protein can predict resistance to Plasmodium falciparum malaria. In this study, 83 adults in a malaria-endemic region of Kenya were tested for circumsporozoite antibodies and then treated for malaria. They were monitored for the development of new malaria infections for 98 days. Antibody levels, as determined by four assays in vitro, were indistinguishable between the 60 individuals who did and the 23 who did not develop parasitemia during follow-up, and there was no apparent relation between day of onset of parasitemia and level of antibodies to circumsporozoite protein. Unless immunization with sporozoite vaccines induces antibodies that are quantitatively or qualitatively superior to the circumsporozoite antibodies in these adults, it is unlikely that such antibodies will prevent infection in areas with as intense malaria transmission as western Kenya.     

African research. Against all odds, victories from the front lines

In one of the world's poorest countries, a team of Malian and American researchers who have been monitoring malaria here since 1997 are attacking malaria both in the lab and in the clinic. The Bandiagara Malaria Project is also laying the groundwork for future trials of a hoped-for vaccine. The researchers' presence has already had a measurable effect: In the past few years, malaria deaths have been rare.     

农业科技援外项目实现“走出去”的实践探讨

农业科研院所以先进科学技术和政府援助项目为依托,实施"走出去"战略,是一条可行的道路。发挥院所科技优势,充分利用"两种资源,两个市场"拓展发展空间,既可以实现科技成果转化,也可使受援国的科研生产水平得到迅速提升。将"走出去"作为一个产业完整链条考虑,由于援助项目的时限性和阶段性,项目结束后如何发展,即能否实现援外项目的可持续发展,是衡量"走出去"是否成功的关键。文章通过北京市农林科学院对外援助项目实践,探讨了一条使援助项目可持续发展的路径。     

Induction of Plasmodium falciparum transmission-blocking antibodies by recombinant vaccinia virus

Many candidate antigens of malaria vaccines have limited immunological recognition. One exception is Pfs25, a cysteine-rich, 25-kilodalton sexual stage surface protein of Plasmodium falciparum. Pfs25 is a target of monoclonal antibodies that block transmission of malaria from vertebrate host to mosquito vector. The surface of mammalian cells infected with a recombinant vaccinia virus that expressed Pfs25 specifically bound transmission-blocking monoclonal antibodies. Furthermore, major histocompatibility complex-disparate congenic mouse strains immunized with recombinant Pfs25 elicited transmission-blocking antibodies, demonstrating that the capacity to develop transmission-blocking antibodies is not genetically restricted in mice. Live recombinant viruses may provide an inexpensive, easily administered alternative to subunit vaccines prepared from purified recombinant proteins to block transmission of malaria in developing countries.     

Genetic loci affecting resistance to human malaria parasites in a West African mosquito vector population

Successful propagation of the malaria parasite Plasmodium falciparum within a susceptible mosquito vector is a prerequisite for the transmission of malaria. A field-based genetic analysis of the major human malaria vector, Anopheles gambiae, has revealed natural factors that reduce the transmission of P. falciparum. Differences in P. falciparum oocyst numbers between mosquito isofemale families fed on the same infected blood indicated a large genetic component affecting resistance to the parasite, and genome-wide scanning in pedigrees of wild mosquitoes detected segregating resistance alleles. The apparently high natural frequency of resistance alleles suggests that malaria parasites (or a similar pathogen) exert a significant selective pressure on vector populations.     

Identification of a platelet membrane glycoprotein as a falciparum malaria sequestration receptor

Infections with the human malaria parasite Plasmodium falciparum are characterized by sequestration of erythrocytes infected with mature forms of the parasite. Sequestration of infected erythrocytes appears to be critical for survival of the parasite and to mediate immunopathological abnormalities in severe malaria. A leukocyte differentiation antigen (CD36) was previously suggested to have a role in sequestration of malaria-infected erythrocytes. CD36 was purified from platelets, where it is known as GPIV, and was shown to be a receptor for binding of infected erythrocytes. Infected erythrocytes adhered to CD36 immobilized on plastic; purified CD36 exhibited saturable, specific binding to infected erythrocytes; and purified CD36 or antibodies to CD36 inhibited and reversed binding of infected erythrocytes to cultured endothelial cells and melanoma cells in vitro. The portion of the CD36 molecule that reverses cytoadherence may be useful therapeutically for rapid reversal of sequestration in cerebral malaria.     

农民工平等就业调研报告

【目的】为了消除农民工劳动就业领域的歧视现象,促进农民工平等就业并尽快融入城市,以期推动中国的城镇化建设。【方法】发放关于农民工平等就业以及就业歧视解决渠道等问题的调查问卷,并对一些企业、法律援助组织等单位进行实地考察。【结果】中国已在农民工平等就业方面取得了明显进步,但是在劳动就业领域农民工依然处于不利地位,面临着"社会保险及福利待遇偏低、间接歧视比较严重、缺乏参与企业民主管理的权利以及社会地位低下"等困境。农民工在劳动就业领域遭遇的各种不公平对待,已经成为农民工融入城市的阻碍,需要引起政府的高度重视。【结论】政府需要通过落实企业内部申诉机制、建立平等委员会、拓宽司法诉讼渠道、强化劳动监察等具体措施,为农民工平等就业提供更加便捷高效的法律救济机制。     

Simian malaria in the Philippines

The first field study of simian malaria in the Philippines found that malaria occurred in 8.6 percent of the animals tested. Although based on a very limited study, this report suggests that the simian reservoir of malaria is probably of limited significance for the human population in the Philippines.     

Qinghaosu (artemisinin): the price of success

Artemisinin and its derivatives have become essential components of antimalarial treatment. These plant-derived peroxides are unique among antimalarial drugs in killing the young intraerythrocytic malaria parasites, thereby preventing their development to more pathological mature stages. This results in rapid clinical and parasitological responses to treatment and life-saving benefit in severe malaria. Artemisinin combination treatments (ACTs) are now first-line drugs for uncomplicated falciparum malaria, but access to ACTs is still limited in most malaria-endemic countries. Improved agricultural practices, selection of high-yielding hybrids, microbial production, and the development of synthetic peroxides will lower prices. A global subsidy would make these drugs more affordable and available. ACTs are central to current malaria elimination initiatives, but there are concerns that tolerance to artemisinins may be emerging in Cambodia.     

Natural microbe-mediated refractoriness to Plasmodium infection in Anopheles gambiae

Malaria parasite transmission depends on the successful transition of Plasmodium through discrete developmental stages in the lumen of the mosquito midgut. Like the human intestinal tract, the mosquito midgut contains a diverse microbial flora, which may compromise the ability of Plasmodium to establish infection. We have identified an Enterobacter bacterium isolated from wild mosquito populations in Zambia that renders the mosquito resistant to infection with the human malaria parasite Plasmodium falciparum by interfering with parasite development before invasion of the midgut epithelium. Phenotypic analyses showed that the anti-Plasmodium mechanism requires small populations of replicating bacteria and is mediated through a mosquito-independent interaction with the malaria parasite. We show that this anti-Plasmodium effect is largely caused by bacterial generation of reactive oxygen species.     

Genetic selection of a Plasmodium-refractory strain of the malaria vector Anopheles gambiae

The anopheline mosquito is the target in most malaria control programs, primarily through the use of residual insecticides. A mosquito was studied that is refractory to most species of malaria through a genetically controlled mechanism. A strain of Anopheles gambiae, which was selected for complete refractoriness to the simian malaria parasite Plasmodium cynomolgi, also has varying degrees of refractoriness to most other malaria species examined, including the human parasites P. falciparum, P. ovale, and P. vivax for which this mosquito is the principal African vector. Furthermore, the refractoriness extends to other subhuman primate malarias, to rodent malaria, and to avian malaria. Refractoriness is manifested by encapsulation of the malaria ookinete after it completes its passage through the mosquito midgut, approximately 16 to 24 hours after ingestion of an infective blood meal. Fully encapsulated ookinetes show no abnormalities in parasite organelles, suggesting that refractoriness is due to an enhanced ability of the host to recognize the living parasite rather than to a passive encapsulation of a dead or dying parasite. Production of fully refractory and fully susceptible mosquito strains was achieved through a short series of selective breeding steps. This result indicates a relatively simple genetic basis for refractoriness. In addition to the value these strains may serve in general studies of insect immune mechanisms, this finding encourages consideration of genetic manipulation of natural vector populations as a malaria control strategy.     

Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations

Plasmodium falciparum chloroquine resistance is a major cause of worldwide increases in malaria mortality and morbidity. Recent laboratory and clinical studies have associated chloroquine resistance with point mutations in the gene pfcrt. However, direct proof of a causal relationship has remained elusive and most models have posited a multigenic basis of resistance. Here, we provide conclusive evidence that mutant haplotypes of the pfcrt gene product of Asian, African, or South American origin confer chloroquine resistance with characteristic verapamil reversibility and reduced chloroquine accumulation. pfcrt mutations increased susceptibility to artemisinin and quinine and minimally affected amodiaquine activity; hence, these antimalarials warrant further investigation as agents to control chloroquine-resistant falciparum malaria.     

Porotic hyperostosis, anemias, malarias, and marshes in the prehistoric Eastern Mediterranean

Porotic hyperostosis, formerly called osteoporosis symmetrica, is an overgrowth of the spongy marrow space of the skull. In children, other bones may also be affected. The disease is a consequence of one of the thalassemias or sicklemia. These anemias are balanced polymorphisms which are apparently maintained by falciparum malaria. Falciparum malaria spread over the anopheline belts of the Old World in coincidence with porotic hyperostosis, but did not penetrate the New World. Here some other parasitism or deficiency anemia must have been the cause of porotic hyperostosis in ancient times. In Anatolia, Greece, and Cyprus from the seventh to second millennia B.C., porotic hyperostosis occurred frequently in early farmers who lived in marshy areas, but rarely in inhabitants of dry or rocky areas or in latest Paleolithic hunters. As shown by skeletal samples from Greece, the frequency of the disease decreased as farming methods improved. However, from Hellenistic to Romantic times it again increased together with increases in the incidence of malaria and in poorer farming. There are correlations between porotic hyperostosis and adult stature and fertility. The mutations producing falciparum malaria therefore must antedate seventh millenium B.C. and I think may have an Eastern Mediterranean origin.