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author:("Liu, weiguan")
1.  Cry1 and Tef gene polymorphisms are associated with Major Depressive Disorder in the Chinese population 
Journal of affective disorders  2013;157:100-103.
Accumulating evidences indicate that circadian abnormalities lead to sleep disorder, neurodegenerative diseases and depression. We have reported that the polymorphisms of a clock-related gene, Tef, contributed to the risk of sleep disturbances and depression in Parkinson disease. The objective of the present study was to examine whether the three clock genes we previous studied are associated with major depressive disorder (MDD) in the Chinese population.
105 subjects with MDD and 485 control subjects participated in this case-control study. Demographics, Mini-mental Status Examination (MMSE), and Hamilton rating scale for depression (HAMD) were obtained in all subjects. Genotypes of SNPs (single nucleotide polymorphism) of Cry1 rs2287161, Cry2 rs10838524 and Tef rs738499 was screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
MDD cases had a significantly higher frequency carrying the C allele and CC genotype in Cry1 rs2287161 and the T allele and TT genotype in Tef rs738499 than controls.
The sample size of MDD group was relatively small.
The polymorphisms of Cry1 rs2287161 and Tef rs738499 are associated to MDD.
PMCID: PMC4058073  PMID: 24581835
Major Depressive Disorder; Circadian rhythm; Clock genes; Cry1; Tef
2.  Inhibitory effect of β-elemene on human breast cancer cells 
It has been approved for the clinical application of β-elemene to treat various cancers mainly brain tumors in China. In the present study, we found that β-elemene significantly inhibited the in vitro growth of human breast cancer cells by inducing apoptosis. In addition, β-elemene also induced the conversion of LC3-I into LC3-II as well as the formation of autolysosomes, indicating the activation of autophagy. Interestingly, inhibition of autophagy significantly potentiated the growth-inhibitory effect of β-elemene on breast cancer cells. In summary, β-elemene induced cytoprotective autophagy in human breast cancer cells in addition to apoptosis. Inhibition of autophagy significantly enhanced the cytotoxicity of β-elemene to human breast cancer cells. Therefore, combination of β-elemene with autophagy inhibitors could be a promising strategy for the treatment of breast cancer.
PMCID: PMC4129006  PMID: 25120771
β-elemene; breast cancer; apoptosis; autophagy
3.  Acceleration of modern acidification in the South China Sea driven by anthropogenic CO2 
Scientific Reports  2014;4:5148.
Modern acidification by the uptake of anthropogenic CO2 can profoundly affect the physiology of marine organisms and the structure of ocean ecosystems. Centennial-scale global and regional influences of anthropogenic CO2 remain largely unknown due to limited instrumental pH records. Here we present coral boron isotope-inferred pH records for two periods from the South China Sea: AD 1048–1079 and AD 1838–2001. There are no significant pH differences between the first period at the Medieval Warm Period and AD 1830–1870. However, we find anomalous and unprecedented acidification during the 20th century, pacing the observed increase in atmospheric CO2. Moreover, pH value also varies in phase with inter-decadal changes in Asian Winter Monsoon intensity. As the level of atmospheric CO2 keeps rising, the coupling global warming via weakening the winter monsoon intensity could exacerbate acidification of the South China Sea and threaten this expansive shallow water marine ecosystem.
PMCID: PMC4042124  PMID: 24888785
4.  Transcriptome Analysis of Shade-Induced Inhibition on Leaf Size in Relay Intercropped Soybean 
PLoS ONE  2014;9(6):e98465.
Multi-species intercropping is a sustainable agricultural practice worldwide used to utilize resources more efficiently. In intercropping systems, short crops often grow under vegetative shade of tall crops. Soybean, one important legume, is often planted in intercropping. However, little is known about the mechanisms of shade inhibition effect on leaf size in soybean leaves at the transcriptome level. We analyzed the transcriptome of shaded soybean leaves via RNA-Seq technology. We found that transcription 1085 genes in mature leaves and 1847 genes in young leaves were significantly affected by shade. Gene ontology analyses showed that expression of genes enriched in polysaccharide metabolism was down-regulated, but genes enriched in auxin stimulus were up-regulated in mature leaves; and genes enriched in cell cycling, DNA-replication were down-regulated in young leaves. These results suggest that the inhibition of higher auxin content and shortage of sugar supply on cell division and cell expansion contribute to smaller and thinner leaf morphology, which highlights potential research targets such as auxin and sugar regulation on leaves for crop adaptation to shade in intercropping.
PMCID: PMC4041726  PMID: 24886785
5.  Hollow-Fiber Pharmacodynamic Studies and Mathematical Modeling To Predict the Efficacy of Amoxicillin for Anthrax Postexposure Prophylaxis in Pregnant Women and Children 
Antimicrobial Agents and Chemotherapy  2013;57(12):5946-5960.
Amoxicillin is considered an option for postexposure prophylaxis of Bacillus anthracis in pregnant and postpartum women who are breastfeeding and in children because of the potential toxicities of ciprofloxacin and doxycycline to the fetus and child. The amoxicillin regimen that effectively kills B. anthracis and prevents resistance is unknown. Fourteen-day dose range and dose fractionation studies were conducted in in vitro pharmacodynamic models to identify the exposure intensity and pharmacodynamic index of amoxicillin that are linked with optimized killing of B. anthracis and resistance prevention. Studies with dicloxacillin, a drug resistant to B. anthracis beta-lactamase, evaluated the role of beta-lactamase production in the pharmacodynamic indices for B. anthracis killing and resistance prevention. Dose fractionation studies showed that trough/MIC and not time above MIC was the index for amoxicillin that was linked to successful outcome through resistance prevention. Failure of amoxicillin regimens was due to inducible or stable high level expression of beta-lactamases. Studies with dicloxacillin demonstrated that a time above MIC of ≥94% was linked with treatment success when B. anthracis beta-lactamase activity was negated. Recursive partitioning analysis showed that amoxicillin regimens that produced peak concentrations of <10.99 μg/ml and troughs of >1.75 μg/ml provided a 100% success rate. Other amoxicillin peak and trough values produced success rates of 28 to 67%. For postpartum and pregnant women and children, Monte Carlo simulations predicted success rates for amoxicillin at 1 g every 8 h (q8h) of 53, 33, and 44% (30 mg/kg q8h), respectively. We conclude that amoxicillin is suboptimal for postexposure prophylaxis of B. anthracis in pregnant and postpartum women and in children.
PMCID: PMC3837908  PMID: 24041894
6.  Mass spectrometric analysis of cerebrospinal fluid protein for glioma and its clinical application 
Contemporary Oncology  2014;18(2):100-105.
Aim of the study
To establish and evaluate the fingerprint diagnostic models of cerebrospinal protein profile in glioma with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and bioinformatics analysis, in order to seek new tumor markers.
Material and methods
SELDI-TOF-MS was used to detect the cerebrospinal protein bond to ProteinChip H4. The cerebrospinal protein profiles were obtained and analyzed using the artificial neural network (ANN) method. Fingerprint diagnostic models of cerebrospinal protein profiles for distinguishing glioma from non-brain-tumor, and distinguishing glioma from benign brain tumor, were established. The support vector machine (SVM) algorithm was used for verification of established diagnostic models. The tumor markers were screened.
In a fingerprint diagnostic model of cerebrospinal protein profiles for distinguishing glioma from non-brain tumor, the sensitivity and specificity of glioma diagnosis were 100% and 91.7%, respectively. Seven candidate tumor markers were obtained. In a fingerprint diagnostic model for distinguishing glioma from benign brain tumor, the sensitivity and specificity of glioma diagnosis were 88.9% and 100%, respectively, and 8 candidate tumor markers were gained.
The combination of SELDI-TOF-MS and bioinformatics tools is a very effective method for screening and identifying new markers of glioma. The established diagnostic models have provided a new way for clinical diagnosis of glioma, especially for qualitative diagnosis.
PMCID: PMC4068817  PMID: 24966792
glioma; cerebrospinal fluid; SELDI-TOF-MS; artificial neural network; support vector machine; diagnostic model; tumor markers
7.  Impact of Meropenem in Combination with Tobramycin in a Murine Model of Pseudomonas aeruginosa Pneumonia 
Pseudomonas aeruginosa pneumonia remains a difficult therapeutic problem. Optimal doses and modes of administration of single agents often do not result in acceptable outcomes. Further, emergence of resistance occurs frequently in this setting with single-agent chemotherapy. The purpose of these experiments was to evaluate combination chemotherapy with meropenem plus tobramycin for P. aeruginosa in a murine pneumonia model. Neutropenia was induced by cyclophosphamide. Pharmacokinetics of meropenem and tobramycin were determined using a population pharmacokinetic approach. Both drugs were given at 4-h intervals. Meropenem was administered as total daily doses of 30 to 600 mg/kg of body weight, while tobramycin doses ranged from 50 to 400 mg/kg. Combination therapy evaluated all combinations of 50, 100, and 150 mg/kg/day of tobramycin doses with 60 or 300 mg/kg/day of meropenem. Total and drug-resistant organisms were enumerated. Meropenem alone had a near-maximal effect at 60 mg/kg/day (3.18 log10 [CFU/g] kill from stasis). The time > MIC in epithelial lining fluid (ELF) at this dose was 35.25% of 24 h. For tobramycin alone, the near-maximal effect was at 150 mg/kg/day and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) in ELF was 240.3. Resistance suppression occurred at an ELF AUC/MIC ratio of 110.6. For combination therapy, the near-maximal effect was reached at 60 mg/kg/day and 50 mg/kg/day of meropenem and tobramycin, which produced a 35.25% time > MIC in ELF and an ELF AUC/MIC ratio of 80.1. The interaction was additive. All combination regimens suppressed resistance. Combination therapy produced additive drug interaction and suppressed all resistance amplification. It is likely that optimal therapy for Pseudomonas aeruginosa pneumonia will involve a combination of agents.
PMCID: PMC3716130  PMID: 23571540
8.  Generation of Doubled Haploid Transgenic Wheat Lines by Microspore Transformation 
PLoS ONE  2013;8(11):e80155.
Microspores can be induced to develop homozygous doubled haploid plants in a single generation. In the present experiments androgenic microspores of wheat have been genetically transformed and developed into mature homozygous transgenic plants. Two different transformation techniques were investigated, one employing electroporation and the other co-cultivation with Agrobacterium tumefaciens. Different tissue culture and transfection conditions were tested on nine different wheat cultivars using four different constructs. A total of 19 fertile transformants in five genotypes from four market classes of common wheat were recovered by the two procedures. PCR followed by DNA sequencing of the products, Southern blot analyses and bio/histo-chemical and histological assays of the recombinant enzymes confirmed the presence of the transgenes in the T0 transformants and their stable inheritance in homozygous T1∶2 doubled haploid progenies. Several decisive factors determining the transformation and regeneration efficiency with the two procedures were determined: (i) pretreatment of immature spikes with CuSO4 solution (500 mg/L) at 4°C for 10 days; (ii) electroporation of plasmid DNA in enlarged microspores by a single pulse of ∼375 V; (iii) induction of microspores after transfection at 28°C in NPB-99 medium and regeneration at 26°C in MMS5 medium; (iv) co-cultivation with Agrobacterium AGL-1 cells for transfer of plasmid T-DNA into microspores at day 0 for <24 hours; and (v) elimination of AGL-1 cells after co-cultivation with timentin (200–400 mg/L).
PMCID: PMC3832437  PMID: 24260351
9.  amoA-encoding archaea and thaumarchaeol in the lakes on the northeastern Qinghai-Tibetan Plateau, China 
All known ammonia-oxidizing archaea (AOA) belong to the phylum Thaumarchaeota within the domain Archaea. AOA possess the diagnostic amoA gene (encoding the alpha subunit of ammonia monooxygenase) and produce lipid biomarker thaumarchaeol. Although the abundance and diversity of amoA gene-encoding archaea (AEA) in freshwater lakes have been well-studied, little is known about AEA ecology in saline/hypersaline lakes. In this study, the distribution of the archaeal amoA gene and thaumarchaeol were investigated in nine Qinghai–Tibetan lakes with a salinity range from freshwater to salt-saturation (salinity: 325 g L-1). The results showed that the archaeal amoA gene was present in hypersaline lakes with salinity up to 160 g L-1. The archaeal amoA gene diversity in Tibetan lakes was different from those in other lakes worldwide, suggesting Tibetan lakes (high elevation, strong ultraviolet, and dry climate) may host a unique AEA population of different evolutionary origin from those in other lakes. Thaumarchaeol was present in all of the studied hypersaline lakes, even in those where no AEA amoA gene was observed. Future research is needed to determine the ecological function of AEA and possible sources of thaumarchaeol in the Qinghai–Tibetan hypersaline lakes.
PMCID: PMC3824093  PMID: 24273535
amoA gene; AEA; Thaumarchaeol; salinity; Qinghai–Tibetan lakes
10.  Antifungal Spectrum, In Vivo Efficacy, and Structure–Activity Relationship of Ilicicolin H 
ACS Medicinal Chemistry Letters  2012;3(10):814-817.
Ilicicolin H is a polyketide—nonribosomal peptide synthase (NRPS)—natural product isolated from Gliocadium roseum, which exhibits potent and broad spectrum antifungal activity, with sub-μg/mL MICs against Candida spp., Aspergillus fumigatus, and Cryptococcus spp. It showed a novel mode of action, potent inhibition (IC50 = 2–3 ng/mL) of the mitochondrial cytochrome bc1 reductase, and over 1000-fold selectivity relative to rat liver cytochrome bc1 reductase. Ilicicolin H exhibited in vivo efficacy in murine models of Candida albicans and Cryptococcus neoformans infections, but efficacy may have been limited by high plasma protein binding. Systematic structural modification of ilicicolin H was undertaken to understand the structural requirement for the antifungal activity. The details of the biological activity of ilicicolin H and structural modification of some of the key parts of the molecule and resulting activity of the derivatives are discussed. These data suggest that the β-keto group is critical for the antifungal activity.
PMCID: PMC4025731  PMID: 24900384
ilicicolin H; Gliocadium roseum; antifungal activity; broad spectrum; cytochrome bc1 reductase inhibitor; in vivo efficacy
11.  Using the Montreal Cognitive Assessment Scale to screen for dementia in Chinese patients with Parkinson's Disease 
Shanghai Archives of Psychiatry  2013;25(5):306-313.
Dementia is one of the most distressing and burdensome health problems associated with Parkinson's Disease (PD). The Montreal Cognitive Assessment scale (MoCA) is widely used to screen for dementia in PD patients, but the appropriate diagnostic cutoff score when used with Chinese PD patients is not known.
Determine a diagnostic cutoff value of the Chinese version of the MoCA (MoCA-C) for Chinese PD patients and describe the characteristics of PD patients screened positive for dementia using the MoCA-C.
The presence of dementia in 616 PD patients and 85 community controls was determined using the Movement Disorder Society Task Force criteria (the gold standard diagnosis). We administered the MoCA-C to these individuals and used a receiver operating characteristic (ROC) curve to identify the cutoff score of the MoCA-C that most efficiently identified dementia in both PD patients and community controls. Demographic and clinical characteristics of PD patients who were screened positive or negative for dementia using the MoCA-C were compared.
A MoCA-C score of 23 was the optimal cutoff score for dementia in both patients and controls. Using this cutoff score, the sensitivity and specificity of the MoCA-C in PD patients were 0.70 and 0.77, respectively; the positive and negative predictive values were 0.59 and 0.85, respectively; and the overall concordance (kappa [95% confidence interval]) was 0.45 (0.39-0.52). The corresponding kappa value (concordance) in community controls was only 0.25 (0.05-0.45). Compared to PD patients who screened negative for dementia, those who screened positive for dementia were significantly impaired in all cognitive domains, including visuospatial and executive functioning, naming, attention, language, abstraction, delayed recall and orientation (all p<0.001). Among the PD patients, screening positive for dementia was independently associated with old age, low educational attainment, female gender and more severe motor impairment.
The commonly recommended cutoff screening score for dementia of 26 on the MoCA it too high for PD patients in China; a cutoff score of 23 is more appropriate. Potential risk factors for dementia in Chinese PD patients include older age, less education, and more severe motor symptoms of PD.
PMCID: PMC4054575  PMID: 24991170
12.  High-resolution summer precipitation variations in the western Chinese Loess Plateau during the last glacial 
Scientific Reports  2013;3:2785.
We present a summer precipitation reconstruction for the last glacial (LG) on the western edge of the Chinese Loess Plateau (CLP) using a well-dated organic carbon isotopic dataset together with an independent modern process study results. Our results demonstrate that summer precipitation variations in the CLP during the LG were broadly correlated to the intensity of the Asian summer monsoon (ASM) as recorded by stalagmite oxygen isotopes from southern China. During the last deglaciation, the onset of the increase in temperatures at high latitudes in the Northern Hemisphere and decline in the intensity of the East Asia winter monsoon in mid latitudes was earlier than the increase in ASM intensity and our reconstructed summer precipitation in the western CLP. Quantitative reconstruction of a single paleoclimatic factor provides new insights and opportunities for further understanding of the paleoclimatic variations in monsoonal East Asia and their relation to the global climatic system.
PMCID: PMC3784955  PMID: 24071743
13.  Growth inhibitory effect of Cucurbitacin E on breast cancer cells 
Objective: Due its inhibitory effects on chemical carcinogenesis and inflammation, Cucurbitacins have been proposed as an effective agent for the prevention or treatment of human cancers. In this study, we aimed to explore the effect of Cucurbitacin E (CuE) on human breast cancer cells. Methods: The inhibitory effect of CuE on proliferation of Bcap37 and MDA-MB-231 cells was assessed by MTT assay. The cell cycle distribution and cell apoptosis were determined by flow cytometry (FCM). The expression of pro-caspase 3, cleaved caspase 3, p21, p27 and the phosphorylation of signaling proteins was detected by Western Blotting. Results: CuE inhibited the growth of human breast cancer cells in a dose and time-dependent manner. FCM analysis showed that CuE induced G2/M phase arrest and cell apoptosis. CuE treatment promoted the cleavage of caspase 3 and upregulated p21 and p27. In addition, the phosphorylation of STAT3 but not ERK-1/2 was abrogated upon CuE treatment. Interestingly, losedose CuE significantly enhanced the growth inhibition induced by cisplatin. Conclusions Cucurbitacin E (CuE) could inhibit the growth of human breast cancer cells in vitro. CuE induced both apoptosis and cell cycle arrest probably through the inhibition of STAT3 function. Lose-dose CuE significantly enhanced the growth inhibitory effect of cisplatin on breast cancer cells, further indicating the potential clinical values of CuE for the prevention or treatment of human breast cancer
PMCID: PMC3759486  PMID: 24040444
Cucurbitacin E; breast cancer; apoptosis
14.  Subjective poor sleep quality in Chinese patients with Parkinson's disease without dementia 
Journal of Biomedical Research  2013;27(4):291-295.
Parkinson's disease (PD) is a common progressive neurological disorder and is composed of motor and non-motor symptoms. Sleep disturbances are frequent problems for patients with PD. The relationship between sleep disturbances with Hoehn and Yahr (H&Y) staging have been demonstrated. However, the relationship between sleep disorders and H&Y is still unclear in patients with PD without dementia in Chinese PD patients. In this study, we interviewed 487 non-demented PD patients of Chinese Han descents by H&Y classification. We found that night sleep quality was significantly associated with the severity of PD (P = 0.008). Panic disorder severity scale (PDSS) total scores were correlated with PD non-motor symptoms scale (PDNMS) scores (r = -0.528, P < 0.001), the Hamilton depression scale (HAMD) scores (r = -0.545, P < 0.001) and the Hamilton anxiety scale (HAMA) scores (r = -0.498, P < 0.001). Our results indicated that sleep quality deteriorated with the advancing of PD in Chinese non-demented patients with PD. Depression and anxiety may partly explain sleep disturbances in non-demented patients with PD.
PMCID: PMC3721037  PMID: 23885268
sleep quality; depression; anxiety; Parkinson disease; non-demented
15.  Interplay between the Westerlies and Asian monsoon recorded in Lake Qinghai sediments since 32 ka 
Scientific Reports  2012;2:619.
Two atmospheric circulation systems, the mid-latitude Westerlies and the Asian summer monsoon (ASM), play key roles in northern-hemisphere climatic changes. However, the variability of the Westerlies in Asia and their relationship to the ASM remain unclear. Here, we present the longest and highest-resolution drill core from Lake Qinghai on the northeastern Tibetan Plateau (TP), which uniquely records the variability of both the Westerlies and the ASM since 32 ka, reflecting the interplay of these two systems. These records document the anti-phase relationship of the Westerlies and the ASM for both glacial-interglacial and glacial millennial timescales. During the last glaciation, the influence of the Westerlies dominated; prominent dust-rich intervals, correlated with Heinrich events, reflect intensified Westerlies linked to northern high-latitude climate. During the Holocene, the dominant ASM circulation, punctuated by weak events, indicates linkages of the ASM to orbital forcing, North Atlantic abrupt events, and perhaps solar activity changes.
PMCID: PMC3431539  PMID: 22943005
16.  Effects of neurotrophin-3 on the differentiation of neural stem cells into neurons and oligodendrocytes 
Neural Regeneration Research  2012;7(19):1483-1487.
In this study, cells from the cerebral cortex of fetal rats at pregnant 16 days were harvested and cultured with 20 μg/L neurotrophin-3. After 7 days of culture, immunocytochemical staining showed that, 22.4% of cells were positive for nestin, 10.5% were positive for β-III tubulin (neuronal marker), and 60.6% were positive for glial fibrillary acidic protein, but no cells were positive for O4 (oligodendrocytic marker). At 14 days, there were 5.6% nestin-, 9.6% β-III tubulin-, 81.1% glial fibrillary acidic protein-, and 2.2% O4-positive cells. In cells not treated with neurotrophin-3, some were nestin-positive, while the majority showed positive staining for glial fibrillary acidic protein. Our experimental findings indicate that neurotrophin-3 is a crucial factor for inducing neural stem cells differentiation into neurons and oligodendrocytes.
PMCID: PMC4308779
neurotrophin-3; neural stem cells; differentiation; neuron; oligodendrocytes; stem cells; neural regeneration
17.  Comparing the Effect of Naturally Restored Forest and Grassland on Carbon Sequestration and Its Vertical Distribution in the Chinese Loess Plateau 
PLoS ONE  2012;7(7):e40123.
Vegetation restoration has been conducted in the Chinese Loess Plateau (CLP) since the 1950s, and large areas of farmland have been converted to forest and grassland, which largely results in SOC change. However, there has been little comparative research on SOC sequestration and distribution between secondary forest and restored grassland. Therefore, we selected typical secondary forest (SF-1 and SF-2) and restored grassland (RG-1 and RG-2) sites and determined the SOC storage. Moreover, to illustrate the factors resulting in possible variance in SOC sequestration, we measured the soil δ13C value. The average SOC content was 6.8, 9.9, 17.9 and 20.4 g kg−1 at sites SF-1, SF-2, RG-1 and RG-2, respectively. Compared with 0–100 cm depth, the percentage of SOC content in the top 20 cm was 55.1%, 55.3%, 23.1%, and 30.6% at sites SF-1, SF-2, RG-1 and RG-2, suggesting a higher SOC content in shallow layers in secondary forest and in deeper layers in restored grassland. The variation of soil δ13C values with depth in this study might be attributed to the mixing of new and old carbon and kinetic fractionation during the decomposition of SOM by microbes, whereas the impact of the Suess effect (the decline of 13C atmospheric CO2 values with the burning of fossil fuel since the Industrial Revolution) was minimal. The soil δ13C value increased sharply in the top 20 cm, which then increased slightly in deeper layers in secondary forest, indicating a main carbon source of surface litter. However the soil δ13C values exhibited slow increases in the whole profile in the restored grasslands, suggesting that the contribution of roots to soil carbon in deeper layers played an important role. We suggest that naturally restored grassland would be a more effective vegetation type for SOC sequestration due to higher carbon input from roots in the CLP.
PMCID: PMC3388043  PMID: 22768335
18.  Differential Effects of Linezolid and Ciprofloxacin on Toxin Production by Bacillus anthracis in an In Vitro Pharmacodynamic System 
Bacillus anthracis causes anthrax. Ciprofloxacin is a gold standard for the treatment of anthrax. Previously, using the non-toxin-producing ΔSterne strain of B. anthracis, we demonstrated that linezolid was equivalent to ciprofloxacin for reducing the total (vegetative and spore) bacterial population. With ciprofloxacin therapy, the total population consisted of spores. With linezolid therapy, the population consisted primarily of vegetative bacteria. Linezolid is a protein synthesis inhibitor, while ciprofloxacin is not. Since toxins are produced only by vegetative B. anthracis, the effect of linezolid and ciprofloxacin on toxin production is of interest. The effect of simulated clinical regimens of ciprofloxacin and linezolid on the vegetative and spore populations and on toxin production was examined in an in vitro pharmacodynamic model over 15 days by using the toxin-producing Sterne strain of B. anthracis. Ciprofloxacin and linezolid reduced the total Sterne population at similar rates. With ciprofloxacin therapy, the total Sterne population consisted of spores. With linezolid therapy, >90% of the population was vegetative B. anthracis. With ciprofloxacin therapy, toxin was first detectable at 3 h and remained detectable for at least 5 h. Toxin was never detected with linezolid therapy. Ciprofloxacin and linezolid reduced the total Sterne population at similar rates. However, the B. anthracis population was primarily spores with ciprofloxacin therapy and was primarily vegetative bacteria with linezolid therapy. Toxin production was detected for at least 5 h with ciprofloxacin therapy but was never detected with linezolid treatment. Linezolid may have an advantage over ciprofloxacin for the treatment of B. anthracis infections.
PMCID: PMC3256020  PMID: 22064542
19.  Pharmacodynamics of β-Lactamase Inhibition by NXL104 in Combination with Ceftaroline: Examining Organisms with Multiple Types of β-Lactamases 
New broad-spectrum β-lactamases such as KPC enzymes and CTX-M-15 enzymes threaten to markedly reduce the utility of our armamentarium of β-lactam agents, even our most potent drugs, such as carbapenems. NXL104 is a broad-spectrum non-β-lactam β-lactamase inhibitor. In this evaluation, we examined organisms carrying defined β-lactamases and identified doses and schedules of NXL104 in combination with the new cephalosporin ceftaroline, which would maintain good bacterial cell kill and suppress resistance emergence for a clinically relevant period of 10 days in our hollow-fiber infection model. We examined three strains of Klebsiella pneumoniae and one isolate of Enterobacter cloacae. K. pneumoniae 27-908M carried KPC-2, SHV-27, and TEM-1 β-lactamases. Its isogenic mutant, K. pneumoniae 4207J, was “cured” of the plasmid expressing the KPC-2 enzyme. K. pneumoniae 24-1318A carried a CTX-M-15 enzyme, and E. cloacae 2-77C expressed a stably derepressed AmpC chromosomal β-lactamase. Dose-ranging experiments for NXL104 administered as a continuous infusion with ceftaroline at 600 mg every 8 h allowed identification of a 24-h area under the concentration-time curve (AUC) for NXL104 that mediated bactericidal activity and resistance suppression. Dose fractionation experiments identified that “time > threshold” was the pharmacodynamic index linked to cell kill and resistance suppression. Given these results, we conclude that NXL104 combined with ceftaroline on an 8-hourly administration schedule would be optimal for circumstances in which highly resistant pathogens are likely to be encountered. This combination dosing regimen should allow for optimal bacterial cell kill (highest likelihood of successful clinical outcome) and the suppression of resistance emergence.
PMCID: PMC3256033  PMID: 22024819
20.  Impact of Granulocytes on the Antimicrobial Effect of Tedizolid in a Mouse Thigh Infection Model▿ 
Antimicrobial Agents and Chemotherapy  2011;55(11):5300-5305.
Tedizolid (TR-700, formerly torezolid) is the active component of the new oxazolidinone prodrug tedizolid phosphate (TR-701). We had previously demonstrated that tedizolid possessed potent antistaphylococcal activity superior to that of linezolid in a neutropenic mouse thigh infection model (A. Louie, W. Liu, R. Kulawy, and G. L. Drusano, Antimicrob. Agents Chemother. 55:3453-3460, 2011). In the current investigation, we used a mouse thigh infection model to delineate the effect of an interaction of TR-700 and granulocytes on staphylococcal cell killing. We compared the antistaphylococcal killing effect of doses of TR-701 equivalent to human exposures ranging from 200 to 3,200 mg/day in both granulocytopenic and normal mice. The mice were evaluated at 24, 48, and 72 h after therapy initiation. In granulocytopenic mice, a clear exposure response in which, depending on the time point of evaluation, stasis was achieved at “human-equivalent” doses of slightly below 2,300 mg/day (at 24 h) to slightly below 2,000 mg/day (at 72 h) was observed. In immune-normal animals, stasis was achieved at human-equivalent doses of slightly greater than 100 mg/day or less. The variance in bacterial cell killing results was attributable to the presence of granulocytes (without drug), the direct effect of TR-700 on Staphylococcus aureus, and the effect of the drug on Staphylococcus aureus mediated through granulocytes. The majority of the bacterial cell killing in normal animals was attributable to the effect of TR-700 mediated through granulocytes. Additional studies need to be undertaken to elucidate the mechanism underlying this observation.
PMCID: PMC3195040  PMID: 21911576
21.  Dose Range Evaluation of Mycograb C28Y Variant, a Human Recombinant Antibody Fragment to Heat Shock Protein 90, in Combination with Amphotericin B-Desoxycholate for Treatment of Murine Systemic Candidiasis ▿ 
Systemic candidiasis causes significant mortality in patients despite amphotericin B (AMB) therapy. Mycograb C28Y variant, a human recombinant antibody fragment to heat shock protein 90, is closely related to Mycograb, which showed a survival advantage in combination with AMB in a phase III human trial. The Mycograb C28Y variant could potentially increase the antifungal effect of AMB. In our study, the interaction between AMB-desoxycholate (DAMB) and the Mycograb C28Y variant was characterized in vitro by using a checkerboard method. Quantitative cultures of kidneys, livers, and spleens of neutropenic mice with systemic Candida albicans infections were used to assess the in vivo interaction between 1.4 mg/kg of body weight/day of DAMB and 0.15, 1.5, and 15 mg/kg/day of the Mycograb C28Y variant after 1, 3, and 5 days of therapy. DAMB and Mycograb C28Y variant monotherapies, vehicle, and a no-treatment arm served as controls. Also, single- and multidose pharmacokinetics for the Mycograb C28Y variant were determined. Indifference or synergy between DAMB and the Mycograb C28Y variant was seen in two trials by the checkerboard method. The pharmacokinetics of the Mycograb C28Y variant was best described by a 2-compartment model with a median serum t1/2α of ∼0.198 h and a t1/2β of ∼1.77 h. In mice, DAMB together with the Mycograb C28Y variant was no more effective than AMB alone (P > 0.05 by analysis of variance). The Mycograb C28Y variant alone had no antifungal activity. We therefore conclude that the Mycograb C28Y variant in combination with DAMB offered no benefit over DAMB monotherapy in a neutropenic murine model of systemic candidiasis.
PMCID: PMC3122395  PMID: 21502626
22.  In Vivo Pharmacodynamics of Torezolid Phosphate (TR-701), a New Oxazolidinone Antibiotic, against Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus Strains in a Mouse Thigh Infection Model ▿ 
Torezolid phosphate (TR-701) is the phosphate monoester prodrug of the oxazolidinone TR-700 which demonstrates potent in vitro activity against Gram-positive bacteria, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The pharmacodynamics of TR-701 or TR-700 (TR-701/700) against S. aureus is incompletely defined. Single-dose pharmacokinetic studies were conducted in mice for TR-701/700. Forty-eight-hour dose range and 24-hour dose fractionation studies were conducted in a neutropenic mouse thigh model of S. aureus infection using MRSA ATCC 33591 to identify the dose and schedule of administration of TR-701/700 that was linked with optimized antimicrobial effect. Additional dose range studies compared the efficacies of TR-701/700 and linezolid for one MSSA strain and one community-associated MRSA strain. In dose range studies, TR-701/700 was equally bactericidal against MSSA and MRSA. Mean doses of 37.6 and 66.9 mg/kg of body weight/day of TR-701/700 resulted in stasis and 1 log CFU/g decreases in bacterial densities, respectively, at 24 h, and mean doses of 35.3, 46.6, and 71.1 mg/kg/day resulted in stasis and 1 and 2 log CFU/g reductions, respectively, at 48 h. Linezolid administered at doses as high as 150 mg/kg/day did not achieve stasis at either time point. Dose fractionation studies demonstrated that the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the pharmacodynamic index for TR-701/700 that was linked with efficacy. TR-701/700 was highly active against MSSA and MRSA, in vivo, and was substantially more efficacious than linezolid, although linezolid's top exposure has half the human exposure. Dose fractionation studies showed that AUC/MIC was the pharmacodynamic index linked with efficacy, indicating that once-daily dosing in humans is feasible.
PMCID: PMC3122459  PMID: 21502615
23.  Comparative Efficacies of Candidate Antibiotics against Yersinia pestis in an In Vitro Pharmacodynamic Model▿ 
Yersinia pestis, the bacterium that causes plague, is a potential agent of bioterrorism. Streptomycin is the “gold standard” for the treatment of plague infections in humans, but the drug is not available in many countries, and resistance to this antibiotic occurs naturally and has been generated in the laboratory. Other antibiotics have been shown to be active against Y. pestis in vitro and in vivo. However, the relative efficacies of clinically prescribed regimens of these antibiotics with streptomycin and with each other for the killing of Yersinia pestis are unknown. The efficacies of simulated pharmacokinetic profiles for human 10-day clinical regimens of ampicillin, meropenem, moxifloxacin, ciprofloxacin, and gentamicin were compared with the gold standard, streptomycin, for killing of Yersinia pestis in an in vitro pharmacodynamic model. Resistance amplification with therapy was also assessed. Streptomycin killed the microbe in one trial but failed due to resistance amplification in the second trial. In two trials, the other antibiotics consistently reduced the bacterial densities within the pharmacodynamic systems from 108 CFU/ml to undetectable levels (<102 CFU/ml) between 1 and 3 days of treatment. None of the comparator agents selected for resistance. The comparator antibiotics were superior to streptomycin against Y. pestis and deserve further evaluation.
PMCID: PMC3101461  PMID: 21486959
24.  Parallel mutual information estimation for inferring gene regulatory networks on GPUs 
BMC Research Notes  2011;4:189.
Mutual information is a measure of similarity between two variables. It has been widely used in various application domains including computational biology, machine learning, statistics, image processing, and financial computing. Previously used simple histogram based mutual information estimators lack the precision in quality compared to kernel based methods. The recently introduced B-spline function based mutual information estimation method is competitive to the kernel based methods in terms of quality but at a lower computational complexity.
We present a new approach to accelerate the B-spline function based mutual information estimation algorithm with commodity graphics hardware. To derive an efficient mapping onto this type of architecture, we have used the Compute Unified Device Architecture (CUDA) programming model to design and implement a new parallel algorithm. Our implementation, called CUDA-MI, can achieve speedups of up to 82 using double precision on a single GPU compared to a multi-threaded implementation on a quad-core CPU for large microarray datasets. We have used the results obtained by CUDA-MI to infer gene regulatory networks (GRNs) from microarray data. The comparisons to existing methods including ARACNE and TINGe show that CUDA-MI produces GRNs of higher quality in less time.
CUDA-MI is publicly available open-source software, written in CUDA and C++ programming languages. It obtains significant speedup over sequential multi-threaded implementation by fully exploiting the compute capability of commonly used CUDA-enabled low-cost GPUs.
PMCID: PMC3138459  PMID: 21672264
25.  Impact of Burden on Granulocyte Clearance of Bacteria in a Mouse Thigh Infection Model ▿  
Antimicrobial Agents and Chemotherapy  2010;54(10):4368-4372.
We wished to delineate granulocytes' impact on the clearance of different bacterial burdens of Pseudomonas aeruginosa and Staphylococcus aureus in a granulocyte-replete mouse thigh infection model. A mouse thigh model was employed. Bacterial challenges from 105 to 3 × 107 CFU (S. aureus) and from 3 × 104 to 3 × 108 CFU (P. aeruginosa) were injected into murine posterior thighs. Organism quantitation was at baseline, 2 h (Pseudomonas only), and 24 h. A Michaelis-Menten population model was fit to the data for each organism. Breakpoints for microbial containment by granulocytes were identified. Bacterial burdens exceeding that breakpoint value resulted in organism multiplication. The Michaelis-Menten model fit the data well. For P. aeruginosa, the observed-predicted plot had a regression equation that explained over 98% of the variance (P ≪ 0.001). For S. aureus, this relationship explained greater than 94% of the variance (P ≪ 0.001). Maximal growth rate constants, maximal population burdens, and the bacterial loads at which granulocytes killed if half-saturated were not different. The kill rate constant for P. aeruginosa was almost 10 times that of S. aureus. Bacterial kill by granulocytes is saturable. No difference between saturation points of different isolates was seen. A higher bacterial burden means an increasing reliance on chemotherapy to drive bacterial clearance.
PMCID: PMC2944594  PMID: 20516275

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