Design,synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer

A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC₅₀ 0.59 μM) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC₅₀ 70 nM) and 84 (IC₅₀ 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC₅₀ of 80 μM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC₅₀ 1.7 μM and 0.27 μM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.     

Minimizing the Livelihood Trade-Offs of Natural Resource Management in the Eastern African Highlands: Policy Implications of a Project in “Creative Governance”

The highlands of Eastern Africa are characterized by high population densities and tightly coupled interactions between adjacent landscape units and users. Effective formal or informal natural resource governance is necessary to mitigate the potential negative social and environmental effects of individuals’ behavior. Yet many natural resource management and development problems that require or benefit from collective solutions remain unresolved (German et al. Environ Dev Sustain 8: 535–552, 2006a; German et al. 2006b; German et al. Q J Int Agr 47(3): 191–216, 2008). We argue that many of the more intractable problems in improving governance stem from the trade-offs that underlie them, which may include a loss of livelihood options for at least some households, leading to governance break down. Following a brief introduction to natural resource management and governance in Eastern Africa, we analyze the results of participatory by-law deliberations by distilling the restrictions proposed governance reforms pose to certain local stakeholders. We recommend that future policy for improved landscape governance couple institutional reforms with livelihood alternatives that reduce the burden of good governance on households.     

A Potential Inhibitory Profile of Liver CD68+ Cells during HCV Infection as Observed by an Increased CD80 and PD-L1 but Not CD86 Expression

AimThe lack of potent innate immune responses during HCV infection might lead to a delay in initiating adaptive immune responses. Kupffer cells (KCs) and liver-infiltrating monocytes/macrophages (CD68⁺ cells) are essential to establish effective anti-HCV responses. They express co-stimulatory molecules, CD80 and CD86. CD86 upregulation induces activator responses that are then potentially regulated by CD80. The relative levels of expression of CD80, CD86 and the inhibitory molecule, PD-L1, on CD68⁺ cells modulate T cell activation. A few studies have explored CD80 and PD-L1 expression on KCs and infiltrating monocytes/macrophages in HCV-infected livers, and none investigated CD86 expression in these cells. These studies have identified these cells based on morphology only. We investigated the stimulatory/inhibitory profile of CD68⁺ cells in HCV-infected livers based on the balance of CD80, CD86 and PD-L1 expression.MethodsCD80, CD86 and PD-L1 expression by CD68⁺ cells in the lobular and portal areas of the liver of chronic HCV-infected (n = 16) and control (n = 14) individuals was investigated using double staining immunohistochemistry.ResultsThe count of CD68⁺ KCs in the lobular areas of the HCV-infected livers was lower than that in the control (p = 0.041). The frequencies of CD68⁺CD80⁺ cells and CD68⁺PD-L1⁺ cells in both lobular and total areas of the liver were higher in HCV-infected patients compared with those in the control group (p = 0.001, 0.031 and 0.007 respectively). Moreover, in the lobular areas of the HCV-infected livers, the frequency of CD68⁺CD80⁺ cells was higher than that of CD68⁺CD86⁺ and CD68⁺PD-L1⁺ cells. In addition, the frequencies of CD68⁺CD80⁺ and CD68⁺CD86⁺ cells were higher in the lobular areas than the portal areas.ConclusionsOur results show that CD68⁺ cells have an inhibitory profile in the HCV-infected livers. This might help explain the delayed T cell response and viral persistence during HCV infection.     

Islands and Stepping-Stones: Comparative Population Structure of Anopheles gambiae sensu stricto and Anopheles arabiensis in Tanzania and Implications for the Spread of Insecticide Resistance

Population genetic structures of the two major malaria vectors Anopheles gambiae s.s. and An. arabiensis, differ markedly across Sub-Saharan Africa, which could reflect differences in historical demographies or in contemporary gene flow. Elucidation of the degree and cause of population structure is important for predicting the spread of genetic traits such as insecticide resistance genes or artificially engineered genes. Here the population genetics of An. gambiae s.s. and An. arabiensis in the central, eastern and island regions of Tanzania were compared. Microsatellite markers were screened in 33 collections of female An. gambiae s.l., originating from 22 geographical locations, four of which were sampled in two or three years between 2008 and 2010. An. gambiae were sampled from six sites, An. arabiensis from 14 sites, and both species from two sites, with an additional colonised insectary sample of each species. Frequencies of the knock-down resistance (kdr) alleles 1014S and 1014F were also determined. An. gambiae exhibited relatively high genetic differentiation (average pairwise F_ST = 0.131), significant even between nearby samples, but without clear geographical patterning. In contrast, An. arabiensis exhibited limited differentiation (average F_ST = 0.015), but strong isolation-by-distance (Mantel test r = 0.46, p = 0.0008). Most time-series samples of An. arabiensis were homogeneous, suggesting general temporal stability of the genetic structure. An. gambiae populations from Dar es Salaam and Bagamoyo were found to have high frequencies of kdr 1014S (around 70%), with almost 50% homozygote but was at much lower frequency on Unguja Island, with no. An. gambiae population genetic differentiation was consistent with an island model of genetic structuring with highly restricted gene flow, contrary to An. arabiensis which was consistent with a stepping-stone model of extensive, but geographically-restricted gene flow.     

Declining responsiveness of Plasmodium falciparum infections to artemisinin-based combination treatments on the Kenyan coast

Background

The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies.

Methods

On the Kenyan coast we studied the treatment responses in 474 children 6–59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995)

Results

The proportion of patients with residual parasitemia on day 1 rose from 55% in 2005–2006 to 87% in 2007–2008 (odds ratio, 5.4, 95%CI, 2.7–11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7–9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005–2006 and 2007–2008 (OR body temperature >37.5°C, 2.8, 1.9–4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof.

Conclusions

The significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates.

Trial Registration

Controlled-Trials.com ISRCTN88705995     

A comparison of minirhizotron,core and monolith methods for quantifying barley (Hordeum vulgare L.) and fababean (Vicia faba L.) root distribution

Root research has been hampered by a lack of good methods and by the amount of time involved in making measurements. The use of the minirhizotron as a quantitative tool requires comparison with conventional destructive methods. This study was conducted in the greenhouse to compare the minirhizotron technique with core and monolith methods in quantifying barley (Hordeum vulgare L.) and fababean (Vicia faba L.) root distribution. Plants were grown in boxes (80 cm long × 80 cm wide × 75 cm deep) in a hexagonal arrangement to minimize the effects of rooting anistrophy. Minirhizotron observations and destructive sampling to a depth of 70 cm using core and monolith methods were performed at the ripening growth stage. Total root length for the entire depth interval was generally higher in barley (159–309 m) than fababean (110–226 m). Significant correlation coefficients between monolith and core methods for root length density (RLD, cm cm^–3) was observed in both crops (p 0.01). A method and depth interaction showed no significant differences in fababean RLD distribution measured by core and monolith methods. However, the RLD was different for the uppermost 40 cm depth in barley. The relationship for RLD between minirhizotron and core methods was significant only in barley (r=0.77^*). For both crops, estimates of RLD in the top 10-cm layer by the minirhizotron technique were lower than those by core and monolith techniques. In contrast, estimates of RLD were higher in fababean at a depth >30 cm. Destructive sampling still remains the method to quantify root growth in the 0–10 cm soil layer. ei]B E Clothier     

Pelvic abscess from enterobius vermicularis. Report of a case with cytologic detection of eggs and worms

BACKGROUND: Enterobius vermicularis is known to produce perianal and ischioanal abscesses and invade the peritoneal cavity via the female reproductive system, causing pelvic peritonitis. However, there are only rare case reports on the cytodiagnosis of these parasitic lesions. CASE: A 28-year-old woman was admitted with a tender left iliac fossa mass and greenish vaginal discharge. Ultrasonogram and computed tomography scan confirmed the presence of a mass lesion suggestive of a tuboovarian abscess. Cytologic examination of the pus obtained during left salpingo-oophorectomy revealed the presence of ova of E vermicularis and fragments of the adult worm in an inflammatory exudate consisting predominantly of neutrophils, eosinophils and occasional epithelioid cell granulomas. Paraffin sections of the tuboovarian mass showed necrotizing epithelioid cell granulomas, but neither ova nor any worm section was identified. Although the possibility of tuberculosis was considered histologically, Ziehl-Neelsen (Z-N) stain for acid-fast bacilli was negative. Z-N staining of the smear and mycobacterial culture of the pus also did not yield positive results. CONCLUSION: E vermicularis may cause tuboovarian abscess with necrotizing epithelioid granulomas mimicking tuberculosis. Cytologic examination of the pus is helpful in the diagnosis.     

外来红树植物无瓣海桑和拉关木在海南东寨港的人工种植与自然扩散

海南东寨港国家级自然保护区拥有我国主要的外来红树植物引种驯化基地,于1985年和1999年分别从孟加拉国和墨西哥引入外来红树植物无瓣海桑(Sonneratia apetala)和拉关木(Laguncularia racemosa)。此后这两个种又从此基地向我国其他沿海湿地再引种,目前已在该岛及华南多处湿地成林,并引发了可能产生对乡土红树植物群落不利影响的担忧。为此,本研究于2019年7月对我国最早引入和种植无瓣海桑和拉关木的东寨港进行这两个种的人工种植与自然扩散的调查,分析它们的扩散路径和扩散趋势,以期为红树林湿地外来植物的管控提供参考。调查结果显示:无瓣海桑人工种植面积为40.56 hm2,主要在试验区和核心区;自然扩散面积40.12 hm2,大部分零散分布于核心区和缓冲区;由于种植次数多、种植地点分散,扩散路径难以判断。拉关木人工种植面积为6.23 hm2,主要在保护水域和试验区;扩散面积0.53 hm2,主要在缓冲区;拉关木已形成的3个主要扩散区在相对集中的种植区外围,可推断其个体呈辐射状向外扩散,扩散的直线距离达3～5 km。扩散区有众多的幼苗个体,显示数量还存在爆发的趋势。两...     

Differences in mate acceptance and host plant recognition between wild and laboratory-reared Busseola fusca (Fuller)

The present study was aimed at characterizing differences in mate acceptance and host plant recognition between Busseola fusca (Lep.: Noctuidae) reared for several generations under laboratory conditions and wild conspecifics, directly collected from maize stems in the field. The mating success was significantly higher in laboratory reared when compared with the wild B. fusca population. Oviposition on artificial stems was significantly higher for laboratory‐reared insects than for the wild ones. Moreover, unlike adults of the wild strain, laboratory‐reared B. fusca showed no preference to oviposit on surrogate stems impregnated with maize extracts. Long‐range attraction to the host plant was significantly lower for laboratory‐reared insects. Furthermore, the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) analysis of mitochondrial DNA showed that the wild type and laboratory populations belonged to the same genetic strain, indicating that these differences between the populations were mainly phenotypic.