Search

The article reports that extreme evolution of animal organs such as elongation of the giraffe's neck has been the focus of intensive research for many decades. Topics include considered that finite element analysis reveals that the enlarged atlanto-occipitalis and intercervical articulations are essential for high-speed head-to-head butting.

This review is on the research literature published in 2013 on topics relating to thermal effects in water pollution control. TIle review is divided into the following sections: membmne preparation and separation, adsorbent preparation and adsorption proces, aerobic biological treatment, anaerobic biological treatment, natural treatment, resource recovery and water environment. [ABSTRACT FROM AUTHOR]

Objective To assess the efficacy of extracorporeal shockwave therapy (ESWT) and provide clinicians with an evidence base for their clinical decision making. Data Sources PubMed, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Evidence-Based Medicine Reviews. Study Selection All randomized or quasi-randomized controlled trials of ESWT for chronic recalcitrant plantar fasciitis were searched. Searching identified 108 potentially relevant articles; of these, 7 studies with 550 participants met inclusion criteria. Data Extraction Number of patients, population, body mass index, duration of symptoms, adverse effects, blinding method, and details of shockwave therapy were extracted. Data Synthesis For intervention success rate, ESWT of low intensity was more effective than control treatment of low intensity. For pain relief, the pooled data showed a significant difference between the ESWT and control groups. For function, only low-intensity ESWT was significantly superior over the control treatment. Conclusions The efficacy of low-intensity ESWT is worthy of recognition. The short-term pain relief and functional outcomes of this treatment are satisfactory. However, owing to the lack of a long-term follow-up, its long-term efficacy remains unknown. [ABSTRACT FROM AUTHOR]

This paper presents a new high-order filter for three-phase grid-connected voltage source converters (VSCs) named the inductor-trap-capacitor-inductor (LTCL) filter, in which multiple LC trap filters are inserted in parallel with the branch of the capacitor in the traditional LCL filter to compose multiple series resonant circuits at the selected frequencies. Particularly, the LTCL filter can attenuate the harmonic currents around the multiples of switching frequencies and guarantee -60 dB/decade attenuation in the high-frequency band, leading to a decrease of the total inductance and volume. Furthermore, within half of the switching frequency range, an LTCL -filter-based grid-connected VSC has almost the same frequency-response characteristic as that with the traditional LCL filter. That is to say, the LTCL filter does not bring any extra control difficulties. The basic parameter selection criteria and the parameter design procedure of the LTCL filter are introduced. Moreover, the sensitivity analysis of the LTCL filter is analyzed and discussed in detail. The comparative analysis and discussion considering the LCL filter, the LLCL filter, the multituned traps filter, and the proposed LTCL filter, have been presented and evaluated through the experiments on a 65-kW three-phase grid-connected VSC prototype. [ABSTRACT FROM AUTHOR]

Microtoid cricetids are widely considered to be the ancestral form of arvicoline rodents, a successful rodent group including voles, lemmings and muskrats. The oldest previously known microtoid cricetid is Microtocricetus molassicus from the Late Miocene (MN9, ca. 10-11 Ma) of Europe. Here, we report a new microtoid cricetid, Primoprismus fejfari gen. et sp. nov., from the Junggar Basin of Xinjiang, northwestern China. The rodent assemblage found in association with this specimen indicates a late Early Miocene age, roughly estimated at 18-17 Ma, and thus more than 6 million years older than M. molassicus. While morphological comparisons suggest that the new taxon is most closely related to M. molassicus, it differs from the latter in a striking combination of primitive characters, including a lower crown, smaller size, a differentiated posterolophid and hypolophid, a faint anterolophid, the absence of an ectolophid, and the presence of a stylid on the labial border of the tooth. Arid conditions prevailing across the mid-latitude interior of Eurasia during the Early Miocene, enhanced by the combined effects of the Tibetan uplift and the gradual retreat of the Tethys Ocean, likely played a role in the appearance of grasslands, which in turn triggered the evolution of microtoid cricetids and, ultimately, the origin of arvicoline rodents. [ABSTRACT FROM AUTHOR]

A new genus and species of aplodontid rodent, Proansomys dureensis, from the late Oligocene of the northern Junggar Basin of China is described. The new genus is referred to as Ansomyinae because the ectoloph on the upper cheek teeth, although not fully crested, has attained the same characteristic bucket-handle-shaped configuration as other members of the subfamily. It represents the earliest record of the subfamily yet discovered in Asia and is more plesiomorphic than species of the genus Ansomys in having a partly crested ectoloph, a lower degree of lophodonty, and less complex tooth basins (lacking accessory lophules). Proansomys has transitional features between Prosciurus and Ansomys, suggesting that the Ansomyinae derived from a group of aplodontids related to Prosciurus, as did other advanced aplodontid rodents. This provides new light on the paleobiogeography of the Ansomyinae. [ABSTRACT FROM AUTHOR]

The timing of the origin and diversification of rodents remains controversial, due to conflicting results from molecular clocks and paleontological data. The fossil record tends to support an early Cenozoic origin of crown-group rodents. In contrast, most molecular studies place the origin and initial diversification of crown-Rodentia deep in the Cretaceous, although some molecular analyses have recovered estimated divergence times that are more compatible with the fossil record. Here we attempt to resolve this conflict by carrying out a molecular clock investigation based on a nine-gene sequence dataset and a novel set of seven fossil constraints, including two new rodent records (the earliest known representatives of Cardiocraniinae and Dipodinae). Our results indicate that rodents originated around 61.7-62.4 Ma, shortly after the Cretaceous/Paleogene (K/Pg) boundary, and diversified at the intraordinal level around 57.7-58.9 Ma. These estimates are broadly consistent with the paleontological record, but challenge previous molecular studies that place the origin and early diversification of rodents in the Cretaceous. This study demonstrates that, with reliable fossil constraints, the incompatibility between paleontological and molecular estimates of rodent divergence times can be eliminated using currently available tools and genetic markers. Similar conflicts between molecular and paleontological evidence bedevil attempts to establish the origination times of other placental groups. The example of the present study suggests that more reliable fossil calibration points may represent the key to resolving these controversies. [ABSTRACT FROM AUTHOR]

The rapid and convenient method for identification of all kinds of G-quadruplex is highly desirable. In the present study, a novel colorimetric indicator for a vast variety of G-quadruplex was designed and synthesized on the basis of thiazole orange and isaindigotone skeleton. Its distinct color change enables label-free visual detection of G-quadruplexes, which is due to the disassembly of dye H-aggregates to monomers. This specific detection of G-quadruplex arises from its end-stacking interaction with G-quartet. On the basis of this universal indicator, a facile approach for large-scale identification of G-quadruplex was developed. [ABSTRACT FROM AUTHOR]

AbstractRecombinant adeno-associated virus (rAAV) vectors offer promise for gene therapy of alpha-1 antitrypsin (AAT) deficiency. A toxicology study in mice evaluated intramuscular injection of an rAAV vector expressing human AAT (rAAV-CB-hAAT) produced using a herpes simplex virus (HSV) complementation system or a plasmid transfection (TFX) method at doses of 3 × 1011vg (1.2 × 1013vg/kg) for both vectors and 2 × 1012vg (8 × 1013vg/kg) for the HSV-produced vector. The HSV-produced vector had favorable in vitrocharacteristics in terms of purity, efficiency of transduction, and hAAT expression. There were no significant differences in clinical findings or hematology and clinical chemistry values between test article and control groups and no gross pathology findings. Histopathological examination demonstrated minimal to mild changes in skeletal muscle at the injection site, consisting of focal chronic interstitial inflammation and muscle degeneration, regeneration, and vacuolization, in vector-injected animals. At the 3 × 1011vg dose, serum hAAT levels were higher with the HSV-produced vector than with the TFX-produced vector. With the higher dose of HSV-produced vector, the increase in serum hAAT levels was dose-proportional in females and greater than dose-proportional in males. Vector copy numbers in blood were highest 24 hr after dosing and declined thereafter, with no detectable copies present 90 days after dosing. Antibodies to hAAT were detected in almost all vector-treated animals, and antibodies to HSV were detected in most animals that received the highest vector dose. These results support continued development of rAAV-CB-hAAT for treatment of AAT deficiency. [ABSTRACT FROM AUTHOR]

The Asian interior has the largest mid-latitude arid zone in the Northern Hemisphere, and so has become increasingly attractive for studying the initiation and the past extent of aridifi cation in this zone. Given the enormousness of the Asian interior, it remains unclear how old and extensive the eolian deposits might have been, and what wind regimes have been responsible for the formation of the mid-latitude arid zone. Here we report new eolian records of widespread Tertiary eolian deposits in a region far from the Chinese Loess Plateau, the giant Junggar inland basin of northwestern China. Our results demonstrate that the earliest eolian deposition initiated ca. 24 Ma. We interpret that the Tertiary eolian dust in the Junggar Basin was transported by westerly winds, possibly from areas in Kazakhstan; the dust differs from the airborne dust transported by winter monsoon winds from the deserts of Mongolia and northern China that accumulated on the Loess Plateau. These results further reveal that the climate pattern, similar to that of the present, has prevailed at least since the latest Oligocene in Central Asia. [ABSTRACT FROM AUTHOR]

The base excision repair (BER) pathway is important in repairing DNA damage incurred from occupational exposure to 1,3-butadiene (BD). This study examines the relationship between inherited polymorphisms of the BER pathway (x-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg280His, Arg399Gln, T-77C, ADPRT Val762Ala, MGMT Leu84Phe and APE1 Asp148Glu) and chromosomal damage in BD-exposed workers, using the cytokinesis-blocked (CB) micronucleus (MN) assay in peripheral lymphocytes of 166 workers occupationally exposed to BD and 41 non-exposed healthy individuals. The MN frequency of exposed workers (3.39 ± 2.42)‰ was higher than that of the non-exposed groups (1.48 ± 1.26)‰ (P < 0.01). Workers receiving greater than median annual BD exposures had higher MN values than lower exposed workers: frequency ratio (FR) of 1.30, 95% confidence interval (CI) 1.14–1.53; P < 0.05. Workers who carried the following genotypes were associated with greater frequency of MN (P < 0.05 for each comparison, unless specified): XRCC1 -77 C/T genotype (FR = 1.28, 95% CI: 1.04–1.57; reference C/C), ADPRT 762 Ala/Ala (FR = 1.54, 95% CI: 1.17–2.03; P < 0.01), XRCC1 194 Arg/Trp (FR = 1.13, 95% CI: 0.87–1.27; reference, Arg/Arg), XRCC1 280 Arg/His (FR = 1.67, 95% CI: 1.10–2.42; reference, Arg/Arg), XRCC1 399 Arg/Gln and Gln/Gln genotypes (FR = 1.26, 95% CI: 1.03–1.53 and FR = 1.24, 95% CI 1.03–1.49; reference Arg/Arg, respectively). As XRCC1 polymorphisms were linked, workers carrying the XRCC1 (-77)-(194)-(280)-(399) diplotype, TCGA/TCGA, had a higher MN frequency compared with individuals carrying the wild-type CCGG/CCGG (FR = 1.57, 95% CI: 1.02–2.41; P < 0.05). In conclusion, CB-MN is a sensitive index of early damage among BD-exposed workers. In workers exposed to BD, multiple BER polymorphisms and a XRCC1 haplotype were associated with differential levels of chromosome damage. [ABSTRACT FROM PUBLISHER]

The Baiyinnuoer deposit (32.74 Mt ore with grades of 5.44% Zn, 2.02% Pb and 31.36 g t−1 Ag), the largest Zn-Pb-Ag deposit in northern China, is hosted by crystalline limestone and slate of the Early Permian Huanggangliang Formation. Detailed cross-section mapping indicates stratigraphic and fold structural controls on the mineralization. The Zn-Pb-Ag mineralization is hosted predominantly by skarn, which occurs as bedding-parallel lens that pinch out at the margins of the main economic zone. Three skarn stages are identified at the deposit: (i) garnet-clinopyroxene; (ii) sulfides; and (iii) carbonate-epidote. Lead isotopic compositions were determined for galena and sphalerite of the ores, whole rock samples of the Yanshanian granite and granodiorite, Permian marble and tuff, and Jurassic volcanic and subvolcanic rocks in and around the Baiyinnuoer area in order to discuss the sources of ore-forming materials and the relationship between the ore formation and these whole rocks. Galena and sphalerite of the Baiyinnuoer ore have uniform isotopic ratios (206Pb/204Pb, 18.267–18.369; 207Pb/204Pb, 15.506–15.624; 208Pb/204Pb, 38.078–38.394) consistent with the granite and granodiorite (206Pb/204Pb, 18.252–18.346; 207Pb/204Pb, 15.504–15.560; 208Pb/204Pb, 38.141–38.320), whereas the ratios for Jurassic volcanic and subvolcanic rocks are variable and radiogenic (206Pb/204Pb, 18.468–18.614; 207Pb/204Pb, 15.521–15.557; 208Pb/204Pb, 38.304–38.375). These results indicate that the mineralization was not related to the Jurassic volcanism, but to the Yanshanian magmatism. The Permian strata may have a slight contribution to the mineralization. All features show that the Baiyinnuoer deposit is related to the Yanshanian granitic magmatism, and can be classified as a zinc-lead-silver skarn deposit. [ABSTRACT FROM AUTHOR]

Abstract??Tertiary marsupial records are very scarce in Asia. A new peradectine marsupial,Junggaroperadectes burqinensisgen. et sp. nov., is reported from the Early Oligocene Keziletuogayi Formation in the Burqin region, Xinjiang, China. This new species is based on a single right upper M2. The tooth possesses a straight centrocrista, a characteristic of peradectines. Its main cusps lean buccally, with the paracone being smaller and lower than the metacone. The conules and stylar cusps are weakly developed. These characters distinguishJ. burqinensisfrom Euro-American Tertiary peradectines, but they also imply a close phylogenetic relationship toSiamoperadectesandSinoperadectes, two Asian Early Miocene peradectines. [ABSTRACT FROM AUTHOR]

An integrated geological and geophysical investigation was carried out in the near-mine areas of the Chaihulanzi gold-field, Inner Mongolia, northern China, to determine the south-eastern strike extension of the principal mineralized shear system, in the search for new resources. In this case study, surface geophysical surveys played an important role in defining the mineralized structures beneath cover. A re-investigation of the mine geology by observing the underground exposures of mineralization and its hosting structures, coupled with re-evaluation and re-examination of previous exploration data, revealed that the mineralization style at the Chaihulanzi gold-field is not the skarn-type as previously assumed, but is structurally controlled by an oblique-sinistral shear structure. Moreover, a south-eastward shallow-plunging mineralized corridor within the principal mineralized shear system was also identified, implying that the ore-forming fluid-flow might move through the mineralizing system, from the south-east at depth to the north-west. These new geological findings imply that the mineralized shear system should extend much farther south-eastwards along strike beneath cover, and thus a conceptual target area was proposed. A detailed geophysical survey program, involving the application of VLF-EM, Stratagem EH4, CSAMT and gradient IP measurements, was carried out to test the validity of the conceptual target. Orientation surveys on the geologically known Line-18 traverse revealed that VLF-EM and Stratagem EH4 were the most effective methods of detecting the unseen mineralized system, whereas CSAMT could only provide low-resolution data, and IP proved to be unsuitable in this environment due to the ubiquitous presence of graphite-bearing schists in and around the mineralized system. A follow-up systematic VLF-EM survey highlighted the principal mineralized shear system as a linear conductive belt, tracing the principal mineralized system for a further 750 m of strike length beneath cover from the previous exploration limit (Line 18). Stratagem EH4 soundings over six parallel traverses perpendicular to the mineralized trend revealed that the principal mineralized shear structure extends for more than 500 m in the dip direction, a strong indication of the presence of potential deep mineralization under the surveyed area. Detailed modelling of the Stratagem EH4 sounding images provided well-defined targets for test drilling. Subsequent test drilling on some of these targets returned encouraging results as several core-intercepts of economic gold mineralization were encountered. This led to a more extensive drilling and underground prospecting program, focusing on deep mineralization south-eastwards along the mineralized trend. [ABSTRACT FROM AUTHOR]

In the first stage of engineering a herpes simplex virus (HSV)-1 that specifically targets human malignant glioma cells, we constructed a recombinant virus designated R5111 in which we have ablated the binding sites for sulfated proteoglycans in glycoproteins B and C, replaced the amino-terminal 148 aa in glycoprotein C by IL-13 flanked at its amino terminus with a signal peptide, and inserted a second copy of IL-13 after the amino acid 24 of glycoprotein D. In the process, the binding site for HveA, a viral entry receptor, was disrupted. We have also transformed a cell line (J1.1) lacking HSV-1 receptors to express IL13Rα2 receptor (J13R cells). We report the following: the R5111 recombinant virus replicates as well as wildtype virus in a variety of cell lines including cell lines derived from brain tumors. R5111 failed to replicate in the parent J1.1 cell line but multiplied to titers similar to those obtained in other cell lines in the J13R cell line. On the basis of the evidence that R5111 can use the IL13Rα2 receptor for entry, we conclude that HSV-1 can use receptors other than HveA or nectins, provided it can bind to them. The domains of gD that interact with HveA and nectin receptors are independent of each other. Lastly, the fusogenic activities of the glycoproteins in the viral envelope are not dependent on a set of unique interactions between glycoprotein D and its receptor. The construction of R5111 opens the way for construction of viruses totally dependent on selected receptors for entry or imaging of targeted cells. [ABSTRACT FROM AUTHOR]

Background. Prediction of high-risk depression trajectories in the first year following breast cancer diagnosis with fMRI-related brain connectomics is unclear. Methods. The Be Resilient to Breast Cancer (BRBC) study is a multicenter trial in which 189/232 participants (81.5%) completed baseline resting-state functional magnetic resonance imaging (rs-fMRI) and four sequential assessments of depression (T0-T3). The latent growth mixture model (LGMM) was utilized to differentiate depression profiles (high vs. low risk) and was followed by multivoxel pattern analysis (MVPA) to recognize distinct brain connectivity patterns. The incremental value of brain connectomics in the prediction model was also estimated. Results. Four depression profiles were recognized and classified into high-risk (delayed and chronic, 14.8% and 12.7%) and low-risk (resilient and recovery, 50.3% and 22.2%). Frontal medial cortex and frontal pole were identified as two important brain areas against the high-risk profile outcome. The prediction model achieved 16.82-76.21% in NRI and 12.63-50.74% in IDI when brain connectomics were included. Conclusion. Brain connectomics can optimize the prediction against high-risk depression profiles in the first year since breast cancer diagnoses. [ABSTRACT FROM AUTHOR]

A technique in measuring torsional vibration signal based on an optical encoder and a discrete wavelet transform is proposed for the extraction of gear meshing characteristics. The method measures the rotation angles of the input and output shafts of a gear pair by using two optical encoders and obtains the time interval sequences of the two shafts. By spline interpolation, the time interval sequences based on uniform angle sampling can be converted into angle interval sequences on the basis of uniform time sampling. The curve of the relative displacement of the gear pair on the meshing line (initial torsional vibration signal) can then be obtained by comparing the rotation angles of the input and output shafts at the interpolated time series. The initial torsional vibration signal is often disturbed by noise. Therefore, a discrete wavelet transform is used to decompose the signal at certain scales; the torsional vibration signal of the gear can then be obtained after filtering. The proposed method was verified by simulation and experimentation, and the results showed that the method could successfully obtain the torsional vibration signal of the gear at a high frequency. The waveforms of the torsional vibration could reflect the meshing characteristics of the teeth. These findings could provide a basis for fault diagnosis of gears. [ABSTRACT FROM AUTHOR]

Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is one of the most devastating diseases in rice (Oryza sativa L.). Plant annexins are calcium- and lipid-binding proteins that have multiple functions; however, the biological roles of annexins in plant disease resistance remain unknown. Here, we report a rice annexin gene, OsANN1 (Rice annexin 1), that was induced by M. oryzae infection and negatively regulated blast disease resistance in rice. By yeast 2-hybrid screening, we found that OsANN1 interacted with a cytochrome P450 monooxygenase, HAN1 ("HAN" termed "chilling" in Chinese), which has been reported to catalyze the conversion of biologically active jasmonoyl-L-isoleucine (JA-Ile) to the inactive form 12-hydroxy-JA-Ile. Pathogen inoculation assays revealed that HAN1 was also a negative regulator in rice blast resistance. Genetic evidence showed that OsANN1 acts upstream of HAN1. OsANN1 stabilizes HAN1 in planta, resulting in the inactivation of the endogenous biologically active JA-Ile. Taken together, our study unravels a mechanism where an OsANN1-HAN1 module impairs blast disease resistance via inactivating biologically active JA-Ile and JA signaling in rice. [ABSTRACT FROM AUTHOR]

Background and Objectives: Mechanically ventilated patients often face progressive and rapid losses of body mass and muscle because of hypermetabolism and increased protein catabolism. To investigate the impact of adequate nutritional provision during the early phase of intensive care unit (ICU) admission on the clinical outcomes in patients with medical illnesses receiving mechanical ventilation support.Methods and Study Design: Two hundred and eleven mechanically ventilated patients admitted to a 30-bed medical ICU were included. Three groups, based on nutrition intake, were examined: adequate protein intake (aPI), n=34; insufficient protein intake/ adequate energy intake (iPI/aEI), n=25; insufficient protein and energy intake (iPI/iEI), n=152.Results: Patients' mean age was 65±14 years; body mass index, 22±4; Acute Physiology and Chronic Health Evaluation II score, 24±7. The aPI group had significantly lower rates of in-ICU (14.7%) and in-hospital (23.5%) mortality than patients with insufficient protein intake: in-ICU mortality, iPI/aEI, 36%; iPI/iEI, 44.1% (p=0.006); in-hospital mortality, iPI/aEI, 56.0%; iPI/iEI, 52.0% (p=0.008). In the multivariate analysis, the hazard ratios (95% confidence intervals) for 60-day survival were 2.59 (1.02-6.59; p=0.046) and 2.88 (1.33-6.26; p=0.008) for the iPI/aEI and iPI/iEI groups, respectively.Conclusions: Despite possible selection bias owing to the retrospective nature of the study, achievement of >90% of target protein intake was associated with improved ICU outcomes in mechanically ventilated critically ill patients, based on real-world clinical circumstances. [ABSTRACT FROM AUTHOR]

The modulation transfer spectroscopy in an ytterbium hollow cathode lamp at 399 nm is measured. The error signal for frequency locking is optimized by measuring the dependences of its slope, linewidth and magnitude on various parameters. Under the optimum condition, the laser frequency at 399 nm can be stabilized. The long-term stability of laser frequency is measured by monitoring the fluorescence signal of the ytterbium atomic beam induced by the locked laser. The laser frequency is shown to be tightly locked, and the stabilized laser is successfully applied to the cooling of ytterbium atoms. [ABSTRACT FROM AUTHOR]

AGTC's proprietary rAAV vector production method uses recombinant herpes simplex virus (HSV) as the helper agent for rAAV production. This production method has been demonstrated to be both highly scalable and productive compared to other rAAV production methods such as the transient co-transfection or adenovirus co-infection process. rAAV production by rHSV-1 methodology requires two recombinant HSV-1 vectors, rHSV-1-rep2cap2 which expresses the AAV 2 rep and cap genes, and a second rHSV-1 that contains the therapeutic gene of interest flanked by the AAV-2 inverted terminal repeats.Both rHSV vectors are deleted in an essential gene for HSV replication and hence they are propagated only in a complementing cell line. Here we report the construction and characterization of rHSV-TR-shFlt-1 that contains a novel soluble hybrid version of Flt-1, the receptor for vascular endothelial growth factor (VEGF). This novel shFlt-1 is a high-affinity binder of VEGF, a central player in pathologic neovascularization in both wet age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR).To construct rHSV-TR-shFlt-1, a shuttle plasmid containing the expression cassette of sFlt-1 flanked with homologous HSV-1 sequences was first constructed and co-transfected with rHSVd27.1-TR-GFP viral DNA into complementing V27 cells. rHSV-TR-shFlt-1 was screened against the parental rHSV-1-GFP viruses that express fluorescent GFP, and the homologous recombination was further confirmed by Southern blot analysis. Selected rHSV-TR-shFlt-1 clones were propagated through 10 passages and their ability to produce rAAV2-TR-shFlt-1 vector was examined by real-time PCR. The expression level, size, and in-vitro biological activity of sFlt-1 expressed in rAAV2-TR-shFlt-1 transduced cells were determined by ELISA, immunoblot, and the HUVECs proliferation assay respectively. Stability studies indicated that the rHSV-TR-shFlt-1 helpers maintained their ability to produce rAAV comparable to that of the positive control rHSV-1-GFP through 10 passages.Preliminary data from the oxygen-induced retinopathy (OIR) mouse model suggests that rAAV2-shFlt-1 derived from rHSV1-TR-shFlt-1 is able to inhibit retinal neovascularization, and there is no significant difference compared to rAAV2-shFlt-1 vector made by the transfection method. To our knowledge this is the first report of the construction and characterization of a recombinant HSV helper virus to produce a rAAV vector encoding a therapeutic gene for inhibition of ocular angiogenesis. Further preclinical evaluation of the AAV2-shFlt-1 is in the process.Molecular Therapy (2006) 13, S194–S194; doi: 10.1016/j.ymthe.2006.08.573 [ABSTRACT FROM AUTHOR]

Background: 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (β-PGG) is a polyphenol ellagic compound with a variety of pharmacological effects and has an inhibitory effect on lots of cancers. Objective: To explore the antitumor effects and mechanism of 1,2,3,4,6-Penta-O-galloyl-β-D-glucose on human hepatocellular carcinoma HepG2 cells. Design: A network pharmacology method was first used to predict the possible inhibition of hepatocellular carcinoma growth by 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (β-PGG) through the p53 signaling pathway. Next, the Cell Counting Kit (CCK-8) assay was performed to evaluate changes in the survival rate of human hepatocellular carcinoma HepG2 cells treated with different concentrations of the drug; flow cytometry was used to detect changes in cell cycle, apoptosis, mitochondrial membrane potential (MMP) and intracellular Ca2+ concentration; real-time fluorescence quantification and immunoblotting showed that the expression of P53 genes and proteins associated with the p53 signaling pathway was significantly increased by β-PGG treatment. Reasult: It was found that β-PGG significantly inhibited survival of HepG2 cells, promoted apoptosis, decreased MMP and intracellular Ca2+ concentration, upregulated P53 gene and protein expression, increased CASP3 expression, and induced apoptosis in HepG2 cells. Conclusion: This study has shown that network pharmacology can accurately predict the target of β-PGG's anti-hepatocellular carcinoma action. Moreover, it was evident that β-PGG can induce apoptosis in HepG2 cells by activating the p53 signaling pathway to achieve its anti-hepatocellular carcinoma effect in vitro. [ABSTRACT FROM AUTHOR]

In natural anoxic environments, anoxygenic photosynthetic bacteria fix CO2 by photoheterotrophy, photoautotrophy, or syntrophic anaerobic photosynthesis. Here, we describe electroautotrophy, a previously unidentified dark CO2 fixation mode enabled by the electrosyntrophic interaction between Geobacter metallireducens and Rhodopseudomonas palustris. After an electrosyntrophic coculture is formed, electrons are transferred either directly or indirectly (via electron shuttles) from G. metallireducens to R. palustris, thereby providing reducing power and energy for the dark CO2 fixation. Transcriptomic analyses demonstrated the high expression of genes encoding for the extracellular electron transfer pathway in G. metallireducens and the Calvin-Benson-Bassham carbon fixation cycle in R. palustris. Given that sediments constitute one of the most ubiquitous and abundant niches on Earth and that, at depth, most of the sedimentary niche is both anoxic and dark, dark carbon fixation provides a metabolic window for the survival of anoxygenic phototrophs, as well as an as-yet unappreciated contribution to the global carbon cycle. [ABSTRACT FROM AUTHOR]

Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and account for a loss of efficacy. To determine whether rAAV vector expression can persist long term, we administered rAAV vectors expressing normal, M-type α-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m. injections. M-specific AAT expression was observed in all subjects in a dose-dependent manner and was sustained for more than 1 year in the absence of immune suppression. Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells compared with 3 month biopsies. Deep sequencing of the TCR Vβ region from muscle biopsies demonstrated a limited number of T cell clones that emerged at 3 months after vector administration and persisted for 1 year. In situ immunophenotyping revealed a substantial Treg population in muscle biopsy samples containing AAT-expressing myofibers. Approximately 10% of all T cells in muscle were natural Tregs, which were activated in response to AAV capsid. These results suggest that i.m. delivery of rAAV type 1-AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing transgene expression and indicates that immunomodulatory treatments may not be necessary for rAAV-mediated gene therapy. [ABSTRACT FROM AUTHOR]

Recombinant adeno-associated virus (rAAV) is an attractive vector for use in gene therapy treatment of various diseases. However, attaining high-level of rAAV has so far been proven problematic and the usefulness of rAAV vectors has been limited by the low production yield with current production methods. Previously we reported a highly scalable method for rAAV serotype 2 (AAV-2) production using two recombinant herpes simplex viruses (rHSV). One rHSV (rHSV-rep2cap2) expresses rep and cap of AAV-2 and provides helper function for AAV replication and packaging, and the other rHSV (rHSV-TR-GFP) contains the reporter gene green fluorescent protein (GFP) flanked by the inverted terminal repeats (ITR) of AAV-2. Both rHSV vectors are replication defective in non complementing cell lines because of the deletion of an essential gene. This rHSV-based system markedly increased the yield of rAAV production when compared to other traditional AAV production methods.It is well known that different serotypes of AAV have distinct host ranges and cell type preferences, and AAV vectors pseudo- typed with serotype one capsid have been shown to be particularly useful in transducing muscle cells. Here we report the development and initial characterization of an rHSV based production system for rAAV-1. Using a replication defective rHSV as the backbone, the AAV-2 Rep and AAV-1 Cap genes were engineered into rHSV by homologous recombination to generate the helper virus rHSV- rep2cap1. The ability of this virus to produce rAAV-1 was tested by co-infecting HEK-293 cells with rHSV-rep2cap1 and rHSV-TR- GFP. AAV genome titers determined by real time PCR showed that rAAV-1-GFP was packaged with a similar efficiency as the positive control rAAV-2-GFP. The infectivity of the produced rAAV-1-GFP was also examined and the results showed that rAAV-1-GFP was able to transduce C12 cells at an expected efficiency when compared to that of AAV-2-GFP. Studies are currently underway to evaluate these rAAV-1 vectors for gene delivery in vivo. In conclusion, this study suggests that the rHSV-based rAAV production system has a great potential for large scale rAAV production of various serotypes and this system may be able to generate sufficient quantities of rAAV for preclinical and clinical applications.Molecular Therapy (2006) 13, S195–S195; doi: 10.1016/j.ymthe.2006.08.576 [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most successful examples of clinical translation of targeted therapies in medical oncology, and this has been demonstrated by their effective management of BRCA1/BRCA2 mutant cancers, most notably in breast and ovarian cancers. PARP inhibitors target DNA repair pathways that BRCA1/2-mutant tumours are dependent upon. Inhibition of the key components of these pathways leads to DNA damage triggering subsequent critical levels of genomic instability, mitotic catastrophe and cell death. This ultimately results in a synthetic lethal relationship between BRCA1/2 and PARP, which underpins the effectiveness of PARP inhibitors. Despite the early and dramatic response seen with PARP inhibitors, patients receiving them often develop treatment resistance. To date, data from both clinical and preclinical studies have highlighted multiple resistance mechanisms to PARP inhibitors, and only by understanding these mechanisms are we able to overcome the challenges. The focus of this review is to summarise the underlying mechanisms underpinning treatment resistance to PARP inhibitors and to aid both clinicians and scientists to develop better clinically applicable assays to better select patients who would derive the greatest benefit as well as develop new novel/combination treatment strategies to overcome these mechanisms of resistance. With a better understanding of PARP inhibitor resistance mechanisms, we would not only be able to identify a subset of patients who are unlikely to benefit from therapy but also to sequence our treatment paradigm to avoid and overcome these resistance mechanisms.

Background and Objectives: Mechanically ventilated patients often face progressive and rapid losses of body mass and muscle because of hypermetabolism and increased protein catabolism. To investigate the impact of adequate nutritional provision during the early phase of intensive care unit (ICU) admission on the clinical outcomes in patients with medical illnesses receiving mechanical ventilation support., Methods and Study Design: Two hundred and eleven mechanically ventilated patients admitted to a 30-bed medical ICU were included. Three groups, based on nutrition intake, were examined: adequate protein intake (aPI), n=34; insufficient protein intake/ adequate energy intake (iPI/aEI), n=25; insufficient protein and energy intake (iPI/iEI), n=152., Results: Patients' mean age was 65±14 years; body mass index, 22±4; Acute Physiology and Chronic Health Evaluation II score, 24±7. The aPI group had significantly lower rates of in-ICU (14.7%) and in-hospital (23.5%) mortality than patients with insufficient protein intake: in-ICU mortality, iPI/aEI, 36%; iPI/iEI, 44.1% (p=0.006); in-hospital mortality, iPI/aEI, 56.0%; iPI/iEI, 52.0% (p=0.008). In the multivariate analysis, the hazard ratios (95% confidence intervals) for 60-day survival were 2.59 (1.02-6.59; p=0.046) and 2.88 (1.33-6.26; p=0.008) for the iPI/aEI and iPI/iEI groups, respectively., Conclusions: Despite possible selection bias owing to the retrospective nature of the study, achievement of >90% of target protein intake was associated with improved ICU outcomes in mechanically ventilated critically ill patients, based on real-world clinical circumstances.