The Greater Mekong Subregion (GMS), comprised of six countries including Cambodia, China's Yunnan Province, Lao PDR, Myanmar (Burma), Thailand and Vietnam, is one of the most threatening foci of malaria. Since the initiation of the WHO's Mekong Malaria Program a decade ago, malaria situation in the GMS has greatly improved, reflected in the continuous decline in annual malaria incidence and deaths. However, as many nations are moving towards malaria elimination, the GMS nations still face great challenges. Malaria epidemiology in this region exhibits enormous geographical heterogeneity with Myanmar and Cambodia remaining high-burden countries. Within each country, malaria distribution is also patchy, exemplified by ‘border malaria’ and ‘forest malaria’ with high transmission occurring along international borders and in forests or forest fringes, respectively. ‘Border malaria’ is extremely difficult to monitor, and frequent malaria introductions by migratory human populations constitute a major threat to neighboring, malaria-eliminating countries. Therefore, coordination between neighboring countries is essential for malaria elimination from the entire region. In addition to these operational difficulties, malaria control in the GMS also encounters several technological challenges. Contemporary malaria control measures rely heavily on effective chemotherapy and insecticide control of vector mosquitoes. However, the spread of multidrug resistance and potential emergence of artemisinin resistance in Plasmodium falciparum make resistance management a high priority in the GMS. This situation is further worsened by the circulation of counterfeit and substandard artemisinin-related drugs. In most endemic areas of the GMS, P. falciparum and P. vivax coexist, and in recent malaria control history, P. vivax has demonstrated remarkable resilience to control measures. Deployment of the only registered drug (primaquine) for the radical cure of vivax malaria is severely undermined due to high prevalence of glucose-6-phosphate dehydrogenase deficiency in target human populations. In the GMS, the dramatically different ecologies, diverse vector systems, and insecticide resistance render traditional mosquito control less efficient. Here we attempt to review the changing malaria epidemiology in the GMS, analyze the vector systems and patterns of malaria transmission, and identify the major challenges the malaria control community faces on its way to malaria elimination.
malaria; the Greater Mekong Subregion; epidemiology; Anopheles vectors; drug resistance; border malaria; elimination
Despite significant improvement in the malaria situation of the Greater Mekong Subregion (GMS), malaria control for the region continues to face a multitude of challenges. The extremely patchy malaria distribution, especially along international borders, makes disease surveillance and targeted control difficult. The vector systems are also diverse with dramatic differences in habitat ecology, biting behavior, and vectorial capacity, and there is a lack of effective transmission surveillance and control tools. Finally, in an era of heavy deployment of artemisinin-based combination therapies, the region acts as an epicenter of drug resistance, with the emergence of artemisinin resistant P. falciparum posing a threat to both regional and global malaria elimination campaigns. This problem is further exacerbated by the circulation of counterfeit and substandard artemisinin drugs. Accordingly, this Southeast Asian Malaria Research Center, consisting of a consortium of US and regional research institutions, has proposed four interlinked projects to address these most urgent problems in malaria control. The aims of these projects will help to substantially improve our understanding of malaria epidemiology, vector systems and their roles in malaria transmission, as well as the mechanisms of drug resistance in parasites. Through the training of next-generation scientists in malaria research, this program will help build up and strengthen regional research infrastructure and capacities, which are essential for sustained malaria control in this region.
malaria; the Greater Mekong Subregion; epidemiology; vector systems; drug resistance; counterfeit drugs
Anopheles sinensis is the most important vector of malaria in Southeast Asia, including China. Currently, the most effective measure to prevent malaria transmission relies on vector control through the use of insecticides, primarily pyrethroids. Extensive use of insecticides poses strong selection pressure on mosquito populations for resistance. Resistance to insecticides can arise due to mutations in the insecticide target site (target site resistance), which in the case of pyrethroids is the para-type sodium channel gene, and/or the catabolism of the insecticide by detoxification enzymes before it reaches its target (metabolic detoxification resistance). In this study, we examined deltamethrin resistance in An. sinensis from China and investigated the relative importance of target site versus metabolic detoxification mechanisms in resistance. A high frequency (>85%) of nonsynonymous mutations in the para gene was found in populations from central China, but not in populations from southern China. Metabolic detoxification as measured by the activity of monooxygenases and glutathione S-transferases (GSTs) was detected in populations from both central and southern China. Monooxygenase activity levels were significantly higher in the resistant than the susceptible mosquitoes, independently of their geographic origin. Stepwise multiple regression analyses in mosquito populations from central China found that both knockdown resistance (kdr) mutations and monooxygenase activity were significantly associated with deltamethrin resistance, with monooxygenase activity playing a stronger role. These results demonstrate the importance of metabolic detoxification in pyrethroid resistance in An. sinensis, and suggest that different mechanisms of resistance could evolve in geographically different populations.
Global climate change caused by greenhouse gas (GHG) emissions, which severely limits the development of human society and threatens the survival of humanity, has drawn the international community's long-term attention. Gathering the most important production factors in the region, an industrial park usually represents the development level of specific industries in the region. Therefore, the industrial park should be regarded as the base unit for developing a low-carbon economy and reducing GHG emissions. Focusing on a typical high-end industrial park in Beijing, we analyze the carbon sources within the system boundary and probe into the emission structure in view of life-cycle analysis. A GHG inventory is thereby set up to calculate all GHG emissions from the concerned park. Based on the results, suggestions are presented to guide the low-carbon development of the high-end industrial park.
The purpose of this study was to evaluate clinical outcomes following one-stage anterior radical debridement, interbody fusion, and sacral rod fixation for the treatment of lumbosacral segment tuberculosis.
From March 2004 to November 2008, 11 patients diagnosed with spinal tuberculosis received antituberculosis medications for two to three weeks before anterior radical debridement, autologous iliac bone grafting, and internal sacral rod fixation. Surgery was performed when the toxic symptoms of tuberculosis were controlled and erythrocyte sedimentation rates (ESR) decreased to 37.2 ± 9.6 mm/h (25–54 mm/h). Lumbosacral angle, visual analogue scale (VAS) pain, ESR, and neurological performance were assessed before and after surgery.
All surgical procedures were performed successfully without intra or postoperative complication. There were no instances of spinal tuberculosis recurrence. Patients were followed-up for a mean of 19.6 months. The mean lumbosacral angle was significantly increased from the mean preoperative angle (12.9 ± 5.0°) both postoperatively (21.5 ± 6.1°) and at final follow-up (20.1 ± 5.2°) (both P <0.001). The mean VAS scores and ESR were significantly decreased from preoperative levels (7.3 ± 1.2 and 37.2 ± 9.6 mm/h, respectively) both postoperatively (1.5 ± 0.5 at month six and 10.4 ± 4.5 mm/h at month three, respectively) and at final follow-up (0.6 ± 0.5 and 10.5 ± 2.3 mm/h, respectively) (all P <0.001). Bone fusion occurred in all patients at a mean of nine months (range six to 12 months) after surgery. Three patients who had impaired neurological performance before surgery had normal neurological performance after surgery.
Our findings suggest that anterior radical debridement, interbody fusion, and sacral rod fixation can be an effective treatment option for lumbosacral segment tuberculosis.
In this paper, a novel direction of arrival (DOA) estimation algorithm called the Toeplitz fourth order cumulants multiple signal classification method (TFOC-MUSIC) algorithm is proposed through combining a fast MUSIC-like algorithm termed the modified fourth order cumulants MUSIC (MFOC-MUSIC) algorithm and Toeplitz approximation. In the proposed algorithm, the redundant information in the cumulants is removed. Besides, the computational complexity is reduced due to the decreased dimension of the fourth-order cumulants matrix, which is equal to the number of the virtual array elements. That is, the effective array aperture of a physical array remains unchanged. However, due to finite sampling snapshots, there exists an estimation error of the reduced-rank FOC matrix and thus the capacity of DOA estimation degrades. In order to improve the estimation performance, Toeplitz approximation is introduced to recover the Toeplitz structure of the reduced-dimension FOC matrix just like the ideal one which has the Toeplitz structure possessing optimal estimated results. The theoretical formulas of the proposed algorithm are derived, and the simulations results are presented. From the simulations, in comparison with the MFOC-MUSIC algorithm, it is concluded that the TFOC-MUSIC algorithm yields an excellent performance in both spatially-white noise and in spatially-color noise environments.
DOA estimation; fourth order cumulants; MUSIC-like; Toeplitz approximation; spatially-white noise; spatially-color noise
Industrial sector is one of the indispensable contributors in global warming. Even if the occurrence of ecoindustrial parks (EIPs) seems to be a good improvement in saving ecological crises, there is still a lack of definitional clarity and in-depth researches on low-carbon industrial parks. In order to reveal the processes of carbon metabolism in a low-carbon high-tech industrial park, we selected Beijing Development Area (BDA) International Business Park in Beijing, China as case study, establishing a seven-compartment- model low-carbon metabolic network based on the methodology of Ecological Network Analysis (ENA). Integrating the Network Utility Analysis (NUA), Network Control Analysis (NCA), and system-wide indicators, we compartmentalized system sectors into ecological structure and analyzed dependence and control degree based on carbon metabolism. The results suggest that indirect flows reveal more mutuality and exploitation relation between system compartments and they are prone to positive sides for the stability of the whole system. The ecological structure develops well as an approximate pyramidal structure, and the carbon metabolism of BDA proves self-mutualistic and sustainable. Construction and waste management were found to be two active sectors impacting carbon metabolism, which was mainly regulated by internal and external environment.
The Millennium Ecosystem Assessment (MA) framework was modified with a special focus on ecosystem service values. A case study of a typical low-carbon industrial park in Beijing was conducted to assess the ecological and economic benefits. The total economic value of this industrial park per year is estimated to be 1.37 × 108 RMB yuan, where the accommodating and social cultural services are the largest two contributors. Due to the construction of small grasslands or green roofs, considerable environmental regulation services are also provided by the park. However, compared with an ecoindustrial park, carbon mitigation is the most prominent service for the low-carbon industrial park. It can be concluded that low-carbon industrial park construction is an efficacious way to achieve coordinated development of society, economy, and environment, and a promising approach to achieving energy saving and carbon reduction.
Along with increasing concerns on environmental protection and global warming mitigation, new industrial organization modes such as “Ecoindustrial Park” and “Low Carbon Industrial Park” are emerging. Since ecoindustrial parks and low carbon industrial parks may offer multifaceted benefits to the users, it naturally follows that the sustainability assessment of the industrial parks ought to adopt a multicriteria methodology. In this paper, a multicriteria sustainable evaluation framework is proposed in combination with the life cycle analysis and applied to a low carbon and high end industrial park (LCHE) in Beijing, China. Results show that the LCHE industrial park can contribute to both energy-saving and greenhouse gas emission mitigations compared with other industrial parks. In terms of economic performance, although the economic profits are considerable, the investment per constructed area is relatively high. The results of sustainable analysis of the LCHE industrial park can thus shed light on future upgrading of industrial parks.
As the major source of greenhouse gas (GHG) emission, cities have been under tremendous pressure of energy conservation and emission reduction for decades. Community is the main unit of urban housing, public facilities, transportation, and other properties of city's land use. The construction of low-carbon community is an important pathway to realize carbon emission mitigation in the context of rapid urbanization. Therefore, an efficient carbon accounting framework should be proposed for CO2 emissions mitigation at a subcity level. Based on life-cycle analysis (LCA), a three-tier accounting framework for the carbon emissions of the community is put forward, including emissions from direct fossil fuel combustion, purchased energy (electricity, heat, and water), and supply chain emissions embodied in the consumption of goods. By compiling a detailed CO2 emission inventory, the magnitude of carbon emissions and the mitigation potential in a typical high-quality community in Beijing are quantified within the accounting framework proposed. Results show that emissions from supply chain emissions embodied in the consumption of goods cannot be ignored. Specific suggestions are also provided for the urban decision makers to achieve the optimal resource allocation and further promotion of low-carbon communities.
Determine the serum levels of endogenous secretory receptor for advanced glycation end products (esRAGEs) in patients with type 2 diabetes and mild cognitive impairment (MCI) and in control patients with type 2 diabetes but no MCI, and examine the relationship of esRAGE and MCI with other clinical factors.
RESEARCH DESIGN AND METHODS
A total of 101 patients with type 2 diabetes who were hospitalized in the Department of Endocrinology at Fujian Provincial Hospital between January 2010 and January 2011 were enrolled. There were 58 patients with MCI and 43 patients without MCI (control). Serum levels of esRAGE were measured using an enzyme-linked immunosorbent assay (ELISA). Other clinical parameters were also measured.
Type 2 diabetic patients with MCI had a longer duration of diabetes; elevated HbA1c, total cholesterol (CHOL), LDL cholesterol (LDL-C), triglyceride (TG), intima-media thickness, C-reactive protein (CRP), and brachial-ankle pulse wave velocity (ba-PWV); and lower ankle brachial index (ABI) and esRAGE relative to the control group. Among patients with MCI, the Montreal Cognitive Assessment (MoCA) score was positively correlated with serum esRAGE but negatively correlated with CHOL. Spearman rank correlation analysis indicated that esRAGE was positively correlated with MoCA score and ABI but negatively correlated with ba-PWV, CHOL, TG, and CRP in all subjects.
Our results suggest that esRAGE may be a potential protective factor for dyslipidemia, atherosclerosis, and MCI in patients with type 2 diabetes.
Her2 overexpression in ER-positive breast cancer cells such as BT474 (BT) cells has been found to confer resistance to tamoxifen, and suppression of Her2 improves the antiproliferative effects of tamoxifen. In this study, the responsiveness to tamoxifen in BT/HerR, Herceptin-resistant BT cell lines established through constant Herceptin exposure, was evaluated. Compared with BT cells, improvement of sensitivity to tamoxifen in BT/HerR was demonstrated by ER functional analysis and cell proliferation assay. Tamoxifen in the resistant cell line was found to inhibit E2-stimulating estrogen-responsive gene pS2 expression more effectively than in BT cells in real time PCR assay. Western analysis showed cross-phosphorylation between ER and downstream components of Her2 was attenuated in BT/HerR cells. ER redistribution from cytoplasm to nucleus could be found in these cells through immunofluorescence and confocal studies and importantly, chromatin immunoprecipitation (ChIP) studies demonstrated that tamoxifen induced occupancy of the pS2 promoter by ER and nuclear receptor corepressor NCoR instead of coactivator AIB1 in these cells. Finally, combination of tamoxifen and Herceptin was found to improve the sensitivity of BT/HerR cells to Herceptin. Our results suggest that the ER genomic pathway in the ER-positive and Herceptin-resistant breast cancer cells may be reactivated, allowing tamoxifen therapy to be effective again, and a combination of tamoxifen and Herceptin can be a potential therapeutic strategy for ER-positive and Herceptin-resistant human breast cancer.
BT474 cells; Her2; ER; cross-talk; Herceptin; tamoxifen; endocrine resistance
A minimal model of cellular mechanosensing system that consists of a single stress fiber adhering on a substrate via two focal adhesions made of catch bonds is adopted to investigate the phenomena of cell reorientation on substrates induced by an applied uniaxial cyclic stretch. The model indicates that the catch bonds in the focal adhesions experience a periodically oscillating internal force with amplitude and frequency controlled by two intrinsic clocks of the stress fiber, one associated with localized activation and the other with homogeneous activation of sarcomere units along the stress fiber. It is shown that this oscillating force due to cyclic stretch tends to destabilize focal adhesions by reducing the lifetime of catch bonds. The resulting slide or relocation of focal adhesions then causes the associated stress fiber to shorten and rotate to configurations nearly perpendicular to the stretching direction. These predicted behaviors from our model are consistent with a wide range of experimental observations.
The variable-stiffness colonoscope (VSC) appears to have advantages over the standard adult colonoscope (SAC), although data are conflicting. To provide a comprehensive up-to-date review, we conducted a meta-analysis to compare the efficacies of the VSC and SAC.
Electronic databases, including PubMed, EMBASE, the Cochrane library and the Science Citation Index, were searched to retrieve relevant trials. In addition, meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies.
Eight randomized controlled trials (RCTs), enrolling a total of 2033 patients, were included in the meta-analysis. There was no significant heterogeneity among these studies. The cecal intubation rate was higher with the use of VSC (RR = 1.03, 95% CI 1.01 to 1.06, 8 RCTs). The VSC was also associated with fewer position changes made during colonoscopy. Time to cecal intubation was similar with VSC and SAC (WMD −0.54, 95% CI −1.40 to 0.32) but shorter in subgroup analysis with the use of VSC (WMD = −1.36, 95% CI −2.29 to −0.43). Sedation dose used with the two types of instruments showed no evidence of differences either. For all trials, only patients were blinded because of the nature of the interventions.
Use of the VSC significantly improved the cecal intubation rate and reduced ancillary maneuvers made during the procedure. Cecal intubation time was similar for the two colonoscope types over all trials, whereas a shortened time with the use of the adult VSC was seen in subgroup analysis.
Colonoscope; Variable-stiffness colonoscope; Stiffness; Meta-analysis
New vessel formation plays a pivotal role in the pathogenesis of neovascular-related diseases. Endothelial progenitor cells (EPCs) were found to contribute to neovascular-related diseases and interference with EPC neovascularization may be a novel target for these diseases. Zoledronate (Zol) was reported to exhibit anti-angiogenic effect. Basing on these evidences, we proposed that Zol may affect EPC function to exert novel anti-angiogenic effect. In this study, we therefore investigated the effects of Zol on multiple aspects of EPC function and explored the underlying mechanisms involved.
EPCs were cultured from bone marrow derived mononuclear cells. The potential effects of Zol on Angiotensin II (Ang II)-stimulated EPC proliferation, migration, adhesion, in vitro tube formation were investigated. The results showed that Ang II (1 µM) enhanced EPC migration, adhesion, in vitro tube formation but had no effect on cell proliferation. Zol (75 and 100 µM) inhibited proliferation of EPCs and 50 µM geranylgeranyol (GGOH) could reverse the decrease of EPC proliferation. We found for the first time that Zol (50–100 µM) dose dependently attenuated migration, adhesion, and in vitro tube formation of EPCs stimulated by Ang II. GGOH could reverse the attenuation of EPC function induced by Zol. However, Zol did not induce EPC apoptosis. In addition, the underlying mechanisms were determined. The results revealed that Zol markedly down-regulated active RhoA stimulated by Ang II and inhibited the phosphorylation of Erk1/2 and JNK. Moreover, RhoA silencing resulted in a notable inhibition of EPC in vitro tube formation, suggesting that RhoA suppression played a pivotal role in Zol antiangiogenic effect.
These findings suggested that Zol attenuated the promotion of EPC function stimulated by Ang II and exhibited novel antiangiogenic effect via RhoA and MAPK signaling. Thus, Zol may be served as a novel therapeutic agent for neovascular-related diseases treatment.
The aim of this study was to observe the regulatory action of the polo-like kinase 1 (PLK1) gene in the invasion of anaplastic thyroid carcinoma cells and investigate its mechanisms. The expression of the PLK1 protein in 36 patients with anaplastic thyroid carcinoma was detected by immunohistochemical staining. siRNA against PLK1 was designed, synthesized and transfected into ARO cells. The effects of PLK1 siRNA on cell invasion were detected by a soft agar colony formation assay and a Transwell chamber assay. The corresponding protein was detected using western blot analysis. The expression of PLK1 in anaplastic thyroid carcinoma samples (67.5±10.6%) was significantly higher compared to that in cancer-adjacent samples (0.65%±0.12%; P<0.01). The expression of PLK1 correlated with clinical stage, lymph node metastasis and prognosis of anaplastic thyroid. The number of cell clones was reduced in a dose-dependent manner with increasing levels of siRNA and the number of cells permeating through the filter membrane decreased following transfection with siRNA. The inhibition of PLK1 caused a significant decrease in CD44v6, matrix metalloproteinase (MMP)-2 and MMP-9 (0.36±0.08, 0.12±0.03, 0.25±0.06, respectively) compared to the non-transfected group (1.15±0.18, 1.21±0.20, 1.25±0.21, respectively; P<0.01). In conclusion, the expression of PLK1 was found to be increased in anaplastic thyroid carcinoma and was correlated with clinical stage, lymph node metastasis and prognosis. Additionaly, PLK1 siRNA was found to inhibit the invasion of anaplastic thyroid carcinoma cells. Therefore, CD44v6, MMP-2 and MMP-9 are likely to be involved in the regulation of cell invasion induced by PLK1.
polo-like kinase 1; anaplastic thyroid carcinoma; RNA interference; cell invasion; matrix metalloproteinase-2; matrix meta-lloproteinase-9; CD44v6
Cell–matrix adhesion depends on the collective behaviours of clusters of receptor–ligand bonds called focal contacts between cell and extracellular matrix. While the behaviour of a single molecular bond is governed by statistical mechanics at the molecular scale, continuum mechanics should be valid at a larger scale. This paper presents an overview of a series of recent theoretical studies aimed at probing the basic mechanical principles of focal contacts in cell–matrix adhesion via stochastic–elastic models in which stochastic descriptions of molecular bonds and elastic descriptions of interfacial traction–separation are unified in a single modelling framework. The intention here is to illustrate these principles using simple analytical and numerical models. The aim of the discussions is to provide possible clues to the following questions: why does the size of focal adhesions (FAs) fall into a narrow range around the micrometre scale? How can cells sense and respond to substrates of varied stiffness via FAs? How do the magnitude and orientation of mechanical forces affect the binding dynamics of FAs? The effects of cluster size, cell–matrix elastic modulus, loading direction and cytoskeletal pretension on the lifetime of FA clusters have been investigated by theoretical arguments as well as Monte Carlo numerical simulations, with results showing that intermediate adhesion size, stiff substrate, cytoskeleton stiffening, low-angle pulling and moderate cytoskeletal pretension are factors that contribute to stable FAs. From a mechanistic point of view, these results provide possible explanations for a wide range of experimental observations and suggest multiple mechanisms by which cells can actively control adhesion and de-adhesion via cytoskeletal contractile machinery in response to mechanical properties of their surroundings.
cell adhesion; focal adhesion; receptor–ligand bond; adhesion lifetime; size effect; stiffness effect
The size of red blood cells (RBC) is on the same order as the diameter of microvascular vessels. Therefore, blood should be regarded as a two-phase flow system of RBCs suspended in plasma rather than a continuous medium of microcirculation. It is of great physiological and pathological significance to investigate the effects of deformation and aggregation of RBCs on microcirculation. In this study, a visualization experiment was conducted to study the microcirculatory behavior of RBCs in suspension. Motion and deformation of RBCs in a microfluidic chip with straight, divergent, and convergent microchannel sections have been captured by microscope and high-speed camera. Meanwhile, deformation and movement of RBCs were investigated under different viscosity, hematocrit, and flow rate in this system. For low velocity and viscosity, RBCs behaved in their normal biconcave disc shape and their motion was found as a flipping motion: they not only deformed their shapes along the flow direction, but also rolled and rotated themselves. RBCs were also found to aggregate, forming rouleaux at very low flow rate and viscosity. However, for high velocity and viscosity, RBCs deformed obviously under the shear stress. They elongated along the flow direction and performed a tank-treading motion.
Red blood cell; Microchannel; Microfluidic chip; Visualization
InAs/GaAs(001) quantum dots grown by droplet epitaxy were investigated using electron microscopy. Misfit dislocations in relaxed InAs/GaAs(001) islands were found to be located approximately 2 nm above the crystalline sample surface, which provides an impression that the misfit dislocations did not form at the island/substrate interface. However, detailed microscopy data analysis indicates that the observation is in fact an artefact caused by the surface oxidation of the material that resulted in substrate surface moving down about 2 nm. As such, caution is needed in explaining the observed interfacial structure.
Quantum dot; Electron microscopy; Misfit dislocations; Droplet epitaxy; Oxidation
Genetic diversity and population structure of Plasmodium vivax parasites are valuable to the prediction of the origin and spread of novel variants within and between populations, and to the program evaluation of malaria control measures. Using two polymorphic genetic markers, the merozoite surface protein genes PvMSP-3α and PvMSP-3β, we investigated the genetic diversity of four Southeast Asian P. vivax populations, representing both subtropical and temperate strains with dramatically divergent relapse patterns. PCR amplification of PvMSP-3α and PvMSP-3β genes detected three and four major size polymorphisms among the 235 infections examined, respectively, while restriction analysis detected 15 and 19 alleles, respectively. Samples from different geographical areas differed dramatically in their PvMSP-3α and PvMSP-3β allele composition and frequency. Samples tended to cluster on the basis of their PCR-RFLP polymorphism. These results indicated that different parasite genotypes were circulating in each endemic area, and that geographic isolation may exist. Multiple infections were detected in all four parasite populations, ranging from 20.5% to 31.8%, strongly indicating that P. vivax populations were highly diverse and multiple clonal infections are common in these malaria-hypoendemic regions of Southeast Asia.
Plasmodium vivax; malaria; merozoite surface protein; diversity; mixed strain infection; Asia
The rapidly increasing amount of public data in chemistry and biology provides new opportunities for large-scale data mining for drug discovery. Systematic integration of these heterogeneous sets and provision of algorithms to data mine the integrated sets would permit investigation of complex mechanisms of action of drugs. In this work we integrated and annotated data from public datasets relating to drugs, chemical compounds, protein targets, diseases, side effects and pathways, building a semantic linked network consisting of over 290,000 nodes and 720,000 edges. We developed a statistical model to assess the association of drug target pairs based on their relation with other linked objects. Validation experiments demonstrate the model can correctly identify known direct drug target pairs with high precision. Indirect drug target pairs (for example drugs which change gene expression level) are also identified but not as strongly as direct pairs. We further calculated the association scores for 157 drugs from 10 disease areas against 1683 human targets, and measured their similarity using a score matrix. The similarity network indicates that drugs from the same disease area tend to cluster together in ways that are not captured by structural similarity, with several potential new drug pairings being identified. This work thus provides a novel, validated alternative to existing drug target prediction algorithms. The web service is freely available at: http://chem2bio2rdf.org/slap.
Modern drug discovery requires the understanding of chemogenomics, the complex interaction of chemical compounds and drugs with a wide variety of protein target and genes in the body. A large amount of data pertaining to such relationships exists in publicly-accessible datasets but it is siloed and thus impossible to use in an integrated fashion. In this work we have integrated and semantically annotated a large amount of public data from a wide range of databases, including compound-gene, drug-drug, protein-protein, drug-side effects and so on, to create a complex network of interactions relating to compounds and protein targets. We developed a statistical algorithm called Semantic Link Association Prediction (SLAP) for predicting “missing links” in this data network: i.e. compound-target interactions for which there is no experimental data but which are statistically probable given the other relationships that exist in this set. We present validation experiments which show this method works with a high degree of accuracy, and also demonstrate how it can be used to create a drug similarity network to make predictions of new indications for existing drugs.
The present study examined mothers’ and fathers’ attributions and attitudes related to parenting in China.
Interviews were conducted with 241 pairs of parents to obtain maternal and paternal reports of attributions regarding successes and failures in parent-child interactions and on progressive versus authoritarian attitudes about parenting.
Mothers’ mean levels of attributions and attitudes did not differ significantly from fathers’ mean levels of attributions and attitudes. Significant correlations were found between mothers’ and fathers’ attributions regarding uncontrollable success, authoritarian attitudes, and modernity of attitudes.
Supporting the cultural evolutionary view that drastic social changes bring about non-conforming and individualistic behavioral tendencies, these findings rectify and expand the existing literature portraying Chinese parenting as uniformly Confucian and traditional.
The murine olfactory system consists of main and accessory systems that perform distinct and overlapping functions. The main olfactory epithelium (MOE) is primarily involved in the detection of volatile odorants, while neurons in the vomeronasal organ (VNO), part of the accessory olfactory system, are important for pheromone detection. During development, the MOE and VNO both originate from the olfactory pit, however, the mechanisms regulating development of these anatomically distinct organs from a common olfactory primordium are unknown. Here we report that two closely related zinc-finger transcription factors FEZF1 and FEZF2 regulate the identity of MOE sensory neurons and are essential for the survival of VNO neurons respectively. Fezf1 is predominantly expressed in the MOE while Fezf2 expression is restricted to the VNO. In Fezf1 deficient mice, olfactory neurons fail to mature and also express markers of functional VNO neurons. In Fezf2 deficient mice, VNO neurons degenerate prior to birth. These results identify Fezf1 and Fezf2 as important regulators of olfactory system development and sensory neuron identity.
main olfactory epithelium; vomeronasal organ; olfactory receptor; vomeronasal receptor; cell fate
Up to date, no consensus has been achieved regarding the possibility of detecting neuronal currents by MRI (ncMRI) in human brain. To evaluate the detectability of ncMRI, an effective way is to simulate ncMRI signal with the realistic neuronal geometry and electrophysiological processes. Unfortunately, previous realistic ncMRI models are based on rat and monkey neurons. The species difference in neuronal morphology and physiology would prevent these models from simulating the ncMRI signal accurately in human subjects. The aim of the present study is to bridge this gap by establishing a realistic ncMRI model specifically for human cerebral cortex. In this model, the ncMRI signal was simulated using anatomically reconstructed human pyramidal neurons and their biophysical properties. The modeling results showed that the amplitude of ncMRI signal significantly depends on the density of synchronously firing neurons and imaging conditions such as position of imaging voxel, direction of main magnetic field (B0) relative to the cortical surface and echo time. The results indicated that physiologically-evoked ncMRI signal is too weak to be detected (magnitude/phase change ≤ -1.4×10−6/0.02°), but the phase signal induced by spontaneous activity may reach a detectable level (up to 0.2°) in favorable conditions.
neuronal current; MRI; human; realistic