Testing parasite ‘intimacy’: the whipworm Trichuris muris in the European house mouse hybrid zone

Host‐parasite interaction studies across hybrid zones often focus on host genetic variation, treating parasites as homogeneous. ‘Intimately’ associated hosts and parasites might be expected to show similar patterns of genetic structure. In the literature, factors such as no intermediate host and no free‐living stage have been proposed as ‘intimacy’ factors likely constraining parasites to closely follow the evolutionary history of their hosts. To test whether the whipworm, Trichuris muris, is intimately associated with its house mouse host, we studied its population genetics across the European house mouse hybrid zone (HMHZ) which has a strong central barrier to gene flow between mouse taxa. T. muris has a direct life cycle and nonmobile free stage: if these traits constrain the parasite to an intimate association with its host we expect a geographic break in the parasite genetic structure across the HMHZ. We genotyped 205 worms from 56 localities across the HMHZ and additionally T. muris collected from sympatric woodmice (Apodemus spp.) and allopatric murine species, using mt‐COX1, ITS1‐5.8S‐ITS2 rDNA and 10 microsatellites. We show four haplogroups of mt‐COX1 and three clear ITS1‐5.8S‐ITS2 clades in the HMHZ suggesting a complex demographic/phylogeographic history. Microsatellites show strong structure between groups of localities. However, no marker type shows a break across the HMHZ. Whipworms from Apodemus in the HMHZ cluster, and share mitochondrial haplotypes, with those from house mice. We conclude Trichuris should not be regarded as an ‘intimate’ parasite of the house mouse: while its life history might suggest intimacy, passage through alternate hosts is sufficiently common to erase signal of genetic structure associated with any particular host taxon.     

New hybrid molecules with anticonvulsant and antinociceptive activity derived from 3-methyl- or 3,3-dimethyl-1-[1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl]pyrrolidine-2,5-diones

The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5–38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the ‘classical’ maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6 Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED₅₀ MES = 74.8 mg/kg, ED₅₀ scPTZ = 51.6 mg/kg, ED₅₀ 6 Hz = 16.8 mg/kg) which showed TD₅₀ = 213.3 mg/kg in the chimney test that yielded satisfying protective indexes (PI MES = 2.85, PI scPTZ = 4.13, PI 6 Hz = 12.70) at time point of 0.5 h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.     

Synthesis and characterization of a photoresponsive doxorubicin/combretastatin A4 hybrid prodrug

To explore the application of photoremovable protecting groups (PPGs) in the field of combination chemotherapy, we designed and synthesized a photoresponsive hybrid prodrug 4 that bearing both doxorubicin (DOX) and combretastatin A4 (CA4). Light triggered drug release investigation found that DOX release was mainly accomplished by 405?nm light while CA4 release was mainly triggered by 365?nm light, i.e., prodrug 4 exhibited a quasi-sequential release behavior when a sequential light irradiation strategy was applied. Cell viability evaluation confirmed the increased cytotoxicity of prodrug 4 compared with individual drugs towards MDA-MB-231cells, indicating that a synergistic effect was achieved.     

Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis

Isoniazid-naphthoquinone hybrids were synthesized and evaluated against a susceptible (H₃₇Rv) strain and two isoniazid-resistant strains (INH_R1 and INH_R2) of Mycobacterium tuberculosis. The antimycobacterial activity of the derivatives was determined based on the resazurin microtiter assay and their cytotoxicity in adhered mouse monocyte macrophage J774.A1 cells (ATCC TIB-67). Of the twenty-two compounds evaluated against the three strains of M. tuberculosis, twenty-one presented some activity against the H₃₇Rv and INH_R1 (katG S315T) or INH_R2 (inhA C(−5)T) strains. Compounds 1a, 2a, and 8a were effective against the INH_R1 strain, and compounds 1a, 1b, 2a, 3a, 5a, 5b and 8a were effective against the INH_R2 strain, with MICs in the range of 3.12–6.25 µg/mL. Compounds 1b and 5b were the most active against H₃₇Rv, with MIC of 0.78 µg/mL. Based on the selectivity index, 1b and 5b can be considered safe as a drug candidate compounds. These results demonstrate that quinoidal compounds can be used as promising scaffolds for the development of new anti-TB drugs and hybrids with activity against M. tuberculosis-susceptible and INH-resistant strains.     

Population structure and the evolution of Homo sapiens in Africa

It has been proposed that a multiregional model could describe how Homo sapiens evolved in Africa beginning 300,000 years ago. Multiregionalism would require enduring morphological or behavioral differences among African regions and morphological or behavioral continuity within each. African fossils, archeology, and genetics do not comply with either requirement and are unlikely to, because climatic change periodically disrupted continuity and reshuffled populations. As an alternative to multiregionalism, I suggest that reshuffling produced novel gene constellations, including one in which the additive or cumulative effect of newly associated genes enhanced cognitive or communicative potential. Eventual fixation of such a constellation in the lineage leading to modern H. sapiens would explain the abrupt appearance of the African Later Stone Age 50–45 thousand years ago, its nearly simultaneous expansion to Eurasia in the form of the Upper Paleolithic, and the ability of fully modern Upper Paleolithic people to swamp or replace non‐modern Eurasians.     

Impact of transient stress and stress enzymes on development

Stress enzymes triggered by transient stress mediate reprioritization of developmental and homeostatic events to flexibly accomplish the next essential developmental event. This review analyzes recent studies on stress and stress enzyme function during early mammalian development and describes the diverse consequences that result from measurement, analysis of function, and management of stress and stress enzymes during development.     

Ecological differentiation and diploid superiority across a moving ploidy contact zone

Plant polyploid complexes provide useful model systems for distinguishing between adaptive and nonadaptive causes of parapatric distributions in closely related lineages. Polyploidy often gives rise to morphological and physiological changes, which may be adaptive to different environments, but separate distributions may also be maintained by reproductive interference caused by postzygotic reproductive isolation. Here, we test the hypothesis that diploid and descendent polyploid races of the wind-pollinated herb Mercurialis annua , which are found in parapatry over an environmental gradient in northeast Spain, are differentiated in their ecophysiology and life history. We also ask whether any such differences represent adaptations to their different natural environments. On the basis of a series of reciprocal transplant experiments in the field, and experiments under controlled conditions, we found that diploid and polyploid populations of M. annua are ecologically differentiated, but that they do not show local adaptation; rather, the diploids have higher fitness than the polyploids across both diploid- and polyploid-occupied regions. In fact, diploids are currently displacing polyploids by advancing south on two separate fronts in Spain, and previous work has shown that this displacement is being driven to a large extent by asymmetrical pollen swamping. Our results here suggest that ecophysiological superiority of the diploids may also be contributing to their expansion.     

The role of the Y chromosome in human evolutionary studies

Analyses of molecular genetic data have added a new dimension to human evolutionary research. Pioneering studies of variation in human populations were based on analyses of blood groups¹ and electromorphs,² both of which represent qualitative multistate phenotypes. With the development of recombinant DNA methods in the 1970s and 1980s, the focus shifted from gene products to a new and plentiful source of human variability, restriction fragment length polymorphisms (RFLPs).^3,4 Finally, the addition of DNA sequencining survey data to the rapidly growing RFLP data base made it feasible for the first time to determine the exact number of nucleotide substitutions between different alleles, as well as to construct gene trees and reconstruct the phylogenetic history of populations.^5–7     

甘蔗ACC氧化酶全长cDNA的克隆及序列分析

ACC氧化酶是高等植物乙烯生物合成途径中的限速酶。根据报道的植物ACC氧化酶基因序列设计特异引物,从甘蔗cDNA文库中克隆到一ACC氧化酶基因片段,命名为GZ-ACO,该基因长792bp,与甘蔗基因组文库中克隆的ACO基因片段仅18个碱基之差。根据该cDNA片段序列,设计两对末端扩增的特异引物,利用RACE-PCR技术,获得GZ-ACO片段的5′端和3′端序列。用VectorNTI7.0软件对三个序列进行拼接和分析,结果得到全长的甘蔗GZ-ACO氧化酶基因。GZ-ACOcDNA核苷酸序列长1307bp,具有一个972bp完整的读码框,启动子ATG位于126bp,终止子TAA位于1097bp,推导编码323个氨基酸。系统进化分析表明,GZ-ACO基因氨基酸序列与其它植物已报道的ACC氧化酶基因具有65%~86%的同源率,且与单子叶禾本科植物首先聚类,其次与单子叶芭蕉科、兰科植物聚类,最后与双子叶植物聚类,与植物形态的系统进化结果一致。该基因已在DDBJ/EMBL/GenBank基因数据库注册,注册号为AY521566。