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We present observations of isotopologue lines of dense-gas tracers at 3 mm and 1 mm towards the nearest ultra-luminous infrared galaxy Arp 220. The 3-mm and 1-mm observations were performed with the Institut de Radioastronomie Millimétrique 30-m telescope and the Atacama Pathfinder Experiment 12-m telescope, respectively. We detected H13CN and HN13C in 1-0 and 3-2, and HC15N 1-0, among which HC15N 1-0 and HN13C 1-0 are detected in Arp 220 for the first time. The H13CO+ 1-0 and 3-2 lines are unlikely to be detected because of the confusion of SiO lines. We find that the ratio of the line brightness temperatures of HN13C 3-2/1-0 is 2.4, which is significantly higher than that of H13CN 3-2/1-0 (0.73). This indicates that HN13C and HNC molecules are in denser regions than H13CN and HCN molecules. With the line ratio of H13CN 1-0 and HC15N 1-0, the 14N/15N ratio was estimated to be 440+140-82, which is larger than that of the local interstellar medium. [ABSTRACT FROM AUTHOR]

The present study aimed to develop a symbiotic selection-marker-free plasmid and host system that would allow successful plasmid maintenance and amplification for use in gene therapy. Initially, the chromosomal aspartate-semialdehyde dehydrogenase (asd) gene was disrupted in DH10B Escherichia coli using Red recombinase-mediated homologous recombination. This method required the use of linear DNA fragments carrying kan-kil genes, and/or homologous extensions to the targeted locus. The resultant auxotrophic cell wall-deficient strain (DH10B?asd) was evaluated as a symbiotic host for amplification of the marker-free plasmid, allowing it to supply ASD activity. In order to construct the plasmid, an asd expression cassette was inserted, under the control of the nirB promoter, into a eukaryotic expression vector, and its kanamycin resistance gene was subsequently removed. The symbiotic plasmid and host system was assessed for numerous plasmid production and stability parameters, including structure, yield, plasmid-retention rate, and bacterial storability, under various conditions. The presence of the plasmid was subsequently confirmed by growth test, restriction enzyme mapping, and sequencing. The plasmid yield and copy number produced in the symbiotic cells, in the absence of antibiotic selection, were shown to be similar to those produced under kanamycin selection, in the cells containing the precursor plasmid and kanamycin resistance gene. Furthermore, the results of the present study demonstrated that when inoculated with <1% inoculant volume, >98% of the cells in the culture retained the plasmid regardless of the number of passages. The strain was stable when stored at -70°C, with negligible viability loss over 12 months. The constructed plasmid is stable and has potential in future gene therapy, while much work is still required. [ABSTRACT FROM AUTHOR]

We have mapped 27 massive star-forming regions associated with water masers using three dense gas tracers: HC³N 10-9, HNC 1-0, and C²H 1-0. The FWHM sizes of HNC clumps and C²H clumps are about 1.5 and 1.6 times higher than those of HC³N, respectively, which can be explained by the fact that HC³N traces more dense gas than HNC and C²H. We found evidence for an increase in the optical depth of C²H with a "radius" from the center to the outer regions in some targets, supporting the chemical model of C²H. The C²H optical depth is found to decline as molecular clouds evolve to a later stage, suggesting that C²H might be used as a "chemical clock" for molecular clouds. The large-scale kinematic structure of clouds was investigated with three molecular lines. All of these sources show significant velocity gradients. The magnitudes of gradient are found to increase toward the inner region, indicating the differential rotation of clouds. Both the ratio of rotational to gravitational energy and the specific angular momentum seem to decrease toward the inner region, implying the obvious angular momentum transfer, which might be caused by magnetic braking. The average magnetic field strength and number density of molecular clouds is derived using the uniform magnetic sphere model. The derived magnetic field strengths range from 3 to 88 µG, with a median value of 13 µG. The mass-to-flux ratio of the molecular cloud is calculated to be much higher than the critical value with derived parameters, which agrees well with numerical simulations. [ABSTRACT FROM AUTHOR]

Metals are thought to have profound effects on the internal structures of the molecular clouds in which stars are born. The absence of metals is expected to prevent gas from efficient cooling and fragmentation in theory. However, this effect has not yet been observed in low-metallicity environments, such as in the early universe and local dwarf galaxies, because of the lack of high-spatial-resolution maps of gas. We carried out Atacama Large Millimeter/submillimeter Array observations of the carbon monoxide (CO) J = 2–1 emission line at 1.4 parsec resolutions of a molecular cloud in DDO 70 at 7% solar metallicity, the most metal-poor galaxy currently known with a CO detection. In total, five clumps have been identified and they are found to more or less follow Larson’s law. Since the CO emission exists in regions with visual extinction AV around 1.0, we converted this AV to the gas-mass surface density using a gas-to-dust ratio of 4594 ± 2848 for DDO 70. We found that the CO clumps in DDO 70 exhibit significantly larger (on average four times) sizes than those at the same gas-mass surface densities in the massive star formation regions of the Milky Way. The existence of such large clumps appears to be consistent with theoretical expectations that gas fragmentation in low-metallicity clouds is suppressed. While our observation is only for one cloud in the galaxy, if it is representative, the above result implies suppressed gas fragmentation during the cloud collapse and star formation in the early universe. [ABSTRACT FROM AUTHOR]

We report the detection of an emission feature at the 12σ level with FWHM line width of about 450 km s−1 toward the nearest quasi-stellar object, QSO Mrk 231. Based on observations with the IRAM 30 m telescope and the Northern Extended Millimeter Array Interferometer, the 11–10 transition of molecular oxygen is the likely origin of the line with rest frequency close to 118.75 GHz. The velocity of the O2 emission in Mrk 231 coincides with the red wing seen in CO emission, suggesting that it is associated with the outflowing molecular gas, located mainly at about 10 kpc away from the central active galactic nucleus (AGN). This first detection of extragalactic molecular oxygen provides an ideal tool to study AGN-driven molecular outflows on dynamic timescales of tens of megayears. O2 may be a significant coolant for molecular gas in such regions affected by AGN-driven outflows. New astrochemical models are needed to explain the implied high molecular oxygen abundance in such regions several kiloparsecs away from the center of galaxies. [ABSTRACT FROM AUTHOR]

We performed a survey in the SiO J = 5 → 4 line toward a sample of 199 Galactic massive star-forming regions at different evolutionary stages with the Submillimeter Telescope (SMT) 10 m and Caltech Submillimeter Observatory (CSO) 10.4 m telescopes. The sample consists of 44 infrared dark clouds (IRDCs), 86 protostellar candidates, and 69 young H ii regions. We detected SiO J = 5 → 4 line emission in 102 sources, with a detection rate of 57%, 37%, and 65% for IRDCs, protostellar candidates, and young H ii regions, respectively. We find both broad line emissions with full widths at zero power >20 km s−1 and narrow line emissions of SiO in objects at various evolutionary stages, likely associated with high-velocity shocks and low-velocity shocks, respectively. The SiO luminosities do not show apparent differences among various evolutionary stages in our sample. We find no correlation between the SiO abundance and the luminosity-to-mass ratio, indicating that the SiO abundance does not vary significantly in regions at different evolutionary stages of star formation. [ABSTRACT FROM AUTHOR]

Glyphosate is the most widely used herbicide in world agriculture and for general vegetation control in a wide range of situations. Global and often intensive glyphosate selection of very large weedy plant populations has resulted in widespread glyphosate resistance evolution in populations of many weed species. Here, working with a glyphosate-resistant (GR) Echinochloa colona population that evolved in a Western Australia agricultural field, we identified an ATP-binding cassette (ABC) transporter (EcABCC8) that is consistently up-regulated in GR plants. When expressed in transgenic rice, this EcABCC8 transporter endowed glyphosate resistance. Equally, rice, maize, and soybean overexpressing the EcABCC8 ortholog genes were made resistant to glyphosate. Conversely, CRISPR/Cas9-mediated knockout of the EcABCC8 ortholog gene OsABCC8 increased rice susceptibility to glyphosate. Subcellular localization analysis and quantification of glyphosate cellular levels in treated ABCC8 transgenic rice plants and isolated leaf protoplasts as well as structural modeling support that EcABCC8 is likely a plasma membrane-localized transporter extruding cytoplasmic glyphosate to the apoplast, lowering the cellular glyphosate level. This is a report of a membrane transporter effluxing glyphosate in a GR plant species, and its function is likely conserved in crop plant species. [ABSTRACT FROM AUTHOR]

Urbanization improves the living environment of billions of people but negatively impacts the local carbon cycle as it encroaches on ecosystems. We analyzed this dual effect of urbanization by quantifying linkages between several indicators -- urbanization-induced terrestrial carbon storage loss (uTCSL), per capita urban area (PCUA), and urban land use efficiency (LCRPGR) -- within the Hohhot-Baotou-Ordos (HBO) region in 1990-2100. Results show that the growth of 4.45 million urban residents and 420.70 km² urban area led to a uTCSL of 815.74 GgC in the HBO region in 1990-2020. The uTCSL contributed to improving the urban crowding indicated by PCUA but was subject to LCRPGR. The PCUA decreased by -33.75 m²/person under high land use efficiency (LCRPGR<1) in 1990-2010. Although the PCUA increased by 23.59 m²/person from 2010 to 2020, it resulted in a 2.08-fold increase in uTCSL compared to 1990-2010, with each additional 1 m² increase in PCUA being associated with carbon storage loss of 24.50 GgC. Our projections indicate that regulating LCRPGR twenty years before the urban population reaches its peak could benefit both uTCSL and PCUA. This study provides valuable insights for urban planning aligned with the UN 2030 Agenda, especially for arid and semi-arid cities. [ABSTRACT FROM AUTHOR]

Objective • The present study aimed to assess the clinical efficacy of acupuncture with the Canggui Tanxue Technique on the Huantiao point for treating sciatica caused by lumbar disc herniation. Methods • This randomized controlled trial evaluated outpatient and inpatient data of patients from the Department of Acupuncture and Encephalopathy at Yancheng City Hospital of Traditional Chinese Medicine, Nanjing University of Traditional Chinese Medicine, between March 2020 and October 2022. A total of 100 eligible cases were recruited. Patients were randomly assigned using a random number table method at a ratio of 1:1 to receive either routine acupuncture technique on the Huantiao point (control group) or Canggui Tanxue Technique on the Huantiao point (Canggui Tanxue group), with 50 cases in each group. Outcome measures included post-treatment pain and clinical efficacy. Results • Canggui Tanxue Technique demonstrated significant pain reduction and improved functional restoration compared to the routine technique, as evidenced by significantly lower scores on the Visual Analogue Scale (VAS), Japanese Orthopaedic Association (JOA) scores, and Roland-Morris Disability Questionnaire (RDQ) scores (P < .05). Patients receiving acupuncture with Canggui Tanxue Technique exhibited significantly higher clinical efficacy compared to those receiving the routine technique (P<.05). Conclusion • Acupuncture with Canggui Tanxue Technique on the Huantiao point provides superior pain reduction and functional restoration for patients with sciatica caused by lumbar disc herniation compared to routine techniques. This approach offers high safety, potent efficiency, and better operability. [ABSTRACT FROM AUTHOR]

An abstract of the article "Current status and considerations on biosimilar in China," by Junzhi Wang is presented.

Potency assays are key to the development, registration, and quality control of biological products. Although previously preferred for clinical relevance, in vivo bioassays have greatly diminished with the advent of dependent cell lines as well as due to ethical concerns. However, for some products, the development of in vitro cell-based assay is challenging, or existing method has limitations such as tedious procedure or low sensitivity. The generation of genetically modified (GM) cell line with improved response to the analyte provides a scientific and promising solution. Potency assays based on GM cell lines are currently used for the quality control of biological products including cytokines, hormones, therapeutic antibodies, vaccines and gene therapy products. In this review, we have discussed the general principles of designing and developing GM cells-based potency assays, including identification of cellular signaling pathways and detectable biological effects, generation of responsive cell lines and constitution of test systems, based on the current research progress. In addition, the applications of some novel technologies and the common concerns regarding GM cells have also been discussed. The research presented in this review provides insights for the development and application of novel GM cells-based potency assays for biological products. • Summarize current progress on genetically modified cells-based potency assays for biological drugs. • Explore general principles of design and development of genetically modified cells-based potency assays. • Discuss concerns on genetically modified cells -based potency assays. [ABSTRACT FROM AUTHOR]

We studied the sulfur chemistry of massive star-forming regions through single-dish submillimeter spectroscopy. OCS, O13CS, 13CS, H2S, and SO transitions were observed toward a sample of massive star-forming regions with embedded UCH ii or CH ii regions. These sources could be divided into H ii-hot core and H ii-only sources based on their CH3CN emission. Our results show that the OCS line of thirteen sources is optically thick, with optical depth ranging from 5 to 16. Column densities of these molecules were computed under LTE conditions. CS column densities were also derived using its optically thin isotopologue 13CS. H2S is likely to be the most abundant gas-phase sulfuretted molecule in hot massive cores. Both the column density and abundance of sulfur-bearing molecules decrease significantly from H ii-hot core to H ii-only sources. Ages derived from hot core models appear to be consistent with star formation theories, suggesting that abundance ratios of [CS]/[SO], [SO]/[OCS], and [OCS]/[CS] could be used as chemical clocks in massive star-forming regions. [ABSTRACT FROM AUTHOR]

60Co γ-ray irradiation-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization at room temperature with 2-cyanoprop-2-yl 1-dithionaphthalate (CPDN) as the chain transfer agent was first applied to acrylonitrile (AN) polymerization, providing a "green" platform for preparing polyacrylonitrile (PAN)-based carbon fibers using an environment-friendly energy source. Various effects of dose rate, molar ratio of the monomer to the chain transfer agent, monomer concentration and reaction time on the AN polymerization behaviors were performed to improve the controllability of molecular the weight and molecular weight distribution of the obtained PAN. The feature of the controlled polymerization was proven by the first-order kinetics, linear increase of the molecular weight with the monomer conversion and a successful chain-extension experiment. The molecular weight and molecular weight distribution of PAN were characterized by size exclusion chromatography (SEC). ¹H NMR and Matrix assisted laser desorption ionization/time of flight mass spectra (MALDI-TOF-MS) confirmed the chain-end functionality of PAN, which also was supported by the successful chain-extension experiments of original PANs with acrylonitrile and styrene as the second monomers respectively. [ABSTRACT FROM AUTHOR]

Background: Both HCV genotypes and viral loads are predictors of therapeutic outcomes among patients treated with α-interferon plus ribavirin; however, such correlation has only been studied for genotypes 1, 2, and 3 but not for genotype 6. Methodology/Findings: 299 voluntary blood donors were recruited who were HCV viremic. Their mean age was 31.8; the male/female ratio was 3.82 (225/59). The viral loads of HCV were measured using the COBAS AmpliPrep/COBAS TaqMan test (CAP/CTM) while HCV genotypes were determined by direct sequencing the partial NS5B region. HCV genotypes 1, 2, 3, and 6 were determined in 48.9%, 8.7%, 12.3%, and 30.1% of the donors, respectively, and the levels of mean viral loads in genotype 1 and 6 significantly higher than that of 2 and 3 (P<0.001). As a whole, the viral loads in male donors were higher than in female (P = 0.006). Moreover, the donors' gender and HCV genotypes are independently correlated with the measured viral loads. Conclusion: HCV genotype 1 and 6 had significantly higher viral loads than genotype 2 and 3. [ABSTRACT FROM AUTHOR]

Using a newly installed system on the 25 m telescope of Urumqi Observatory, we searched for H2O maser emission towards 84 IRAS sources including young stellar objects (YSOs) and candidates for OH/IR stars. Water masers were detected in four star formation regions and one envelope of late type of stars for the first time. New water maser components were measured in two sources. In a maser source with no water maser emission detected six years ago, strong maser emission was found at different velocities, showing that there was a new explosion of water maser in this source. [ABSTRACT FROM AUTHOR]

We report the detection of widespread CH2OHCHO and HOCH2CH2OH emission in Galactic center giant molecular cloud Sagittarius B2 using the Shanghai Tianma 65 m Radio Telescope. Our observations show for the first time that the spatial distribution of these two important prebiotic molecules extends over 15 arcmin, corresponding to a linear size of approximately 36 pc. These two molecules are not just distributed in or near the hot cores. The abundance of these two molecules seems to decrease from the cold outer region to the central region associated with star formation activity. Results presented here suggest that these two molecules are likely to form through a low temperature process. Recent theoretical and experimental studies demonstrated that prebiotic molecules can be efficiently formed in icy grain mantles through several pathways. However, these complex ice features cannot be directly observed, and most constraints on the ice compositions come from millimeter observations of desorbed ice chemistry products. These results, combined with laboratory studies, strongly support the existence of abundant prebiotic molecules in ices. [ABSTRACT FROM AUTHOR]

We have compiled a sample of 26 metal-poor galaxies with 12 + log(O/H) < 8.1 with both infrared continuum and 1.4 GHz radio continuum data. By comparing to galaxies at higher metallicity, we have investigated the IR–radio relationship’s dependence on metallicity at the 24, 70, 100, and 160 μm bands, as well as the integrated FIR luminosity. It is found that metal-poor galaxies have on average lower than metal-rich ones, with larger offsets at longer IR wavelengths, from −0.06 dex in to −0.6 dex in . The of all galaxies as a whole at 160 μm show positive trends with the metallicity and IR-to-FUV ratio and negative trends with the IR color, while those at lower IR wavelengths show weaker correlations. We propose a mechanism that invokes the combined effects of low obscured-SFR-to-total-SFR fraction and warm dust temperature at low metallicity to interpret the above behavior of , with the former reducing the IR radiation and the latter further reducing the IR emission at longer IR wavelengths. Other mechanisms that are related to the radio emission, including the enhanced magnetic field strength and increased thermal radio contribution, are unable to reconcile the IR-wavelength-dependent differences of between metal-poor and metal-rich galaxies. In contrast to , the mean total-SFR-to-radio ratio of metal-poor galaxies is the same as that for metal-rich galaxies, indicating the 1.4 GHz radio emission is still an effective tracer of SFRs at low metallicity. [ABSTRACT FROM AUTHOR]

As human uricase has been silenced during evolution, counterparts from other species become an alternative for the treatment of hyperuricemia. Candida uricase is a promising option among them, but its aggregation propensity remains a major obstacle to clinical use. In this study, we designed two mutations according to homology-modeled 3D structure of Candida uricase: Cys249Ser substitution and C-terminal Leu deletion. The wild-type uricase and three mutants containing either or both of the mutations were expressed in Escherichia coli BL21 and validated by mass spectrometry. Size-exclusion chromatography and electrophoresis analysis demonstrated that aggregation was induced by interchain disulfide bonds and could be significantly avoided by Cys249Ser substitution. In combination with Cys249Ser substitution, deletion of Leu increased the enzymatic activity by 8%. Taken together, mutant containing both mutations is chosen as our target protein which is comparatively more suitable for therapeutic use. In addition, homology-modeled 3D structure was proved to be an efficient approach for protein engineering. [ABSTRACT FROM AUTHOR]

Hepatitis A virus (HAV) infects ~1.4 million people annually and, although there is a vaccine, there are no licensed therapeutic drugs. HAV is unusually stable (making disinfection problematic) and little is known of how it enters cells and releases its RNA. Here we report a potent HAV-specific monoclonal antibody, R10, which neutralizes HAV infection by blocking attachment to the host cell. High-resolution cryo-EM structures of HAV full and empty particles and of the complex of HAV with R10 Fab reveal the atomic details of antibody binding and point to a receptor recognition site at the pentamer interface. These results, together with our observation that the R10 Fab destabilizes the capsid, suggest the use of a receptor mimic mechanism to neutralize virus infection, providing new opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background. The development of a Sabin strain-based inactivated poliovirus vaccine (Sabin-IPV) is imperative to protecting against vaccine-associated paralytic poliomyelitis in developing countries. Methods. In this double-blinded, parallel-group, noninferiority trial, eligible infants aged 60-90 days were randomly assigned in a ratio of 1:1 to receive either 3 doses of Sabin-IPV or Salk strain-based IPV (Salk-IPV) at 30-day intervals and a booster at the age of 18 months. Immunogenicity and safety were assessed on the basis of a protocol. Results. Of 1438 infants, 1200 eligible infants were recruited and received either Sabin-IPV or Salk-IPV. From the Sabin-IPV and Salk-IPV groups, 570 and 564 infants, respectively, completed the primary immunization and formed the per-protocol population. The seroconversion rates of the participants who received Sabin-IPV were 100%, 94.9%, and 99.0% (types I, II, and III, respectively), and those of the participants who received Salk-IPV were 94.7%, 91.3%, and 97.9% 1 month after the completion of primary immunization. An anamnestic response for poliovirus types I, II, and III was elicited by a booster in both groups. Except in the case of fever, other adverse events were similar between the 2 groups. Conclusions. The immune response induced by Sabin-IPV was not inferior to that established with Salk-IPV. [ABSTRACT FROM AUTHOR]

We report Shanghai Tian Ma Radio Telescope (TMRT) detections of several long carbon-chain molecules in the C and Ku bands, including HC3N, HC5N, HC7N, HC9N, C3S, C6H, and C8H toward the starless cloud Serpens South 1a. We detected some transitions (HC9N J = 13–12, F = 12–11, and F = 14–13; H13CCCN J = 2–1, F = 1–0, and F = 1–1; HC13CCN J = 2–1, F = 2–2, F = 1–0, and F = 1–1; HCC13CN J = 2–1, F = 1–0, and F = 1–1) and resolved some hyperfine components (HC5N J = 6–5, F = 5–4; H13CCCN J = 2–1, F = 2–1) for the first time in the interstellar medium. The column densities of these carbon-chain molecules in the range 1012–1013 cm−2 are comparable to two carbon-chain molecule rich sources, TMC-1 and Lupus-1A. The abundance ratios are 1.00:(1.11 ± 0.15):(1.47 ± 0.18) for [H13CCCN]:[HC13CCN]:[HCC13CN]. This result implies that the 13C isotope is also concentrated in the carbon atom adjacent to the nitrogen atom in HC3N in Serpens South 1a, which is similar to TMC-1. The [HC3N]/[H13CCCN] ratio of 78 ± 9, the [HC3N]/[HC13CCN] ratio of 70 ± 8, and the [HC3N]/[HCC13CN] ratio of 53 ± 4 are also comparable to those in TMC-1. Serpens South 1a proves to be a suitable testing ground for understanding carbon-chain chemistry. [ABSTRACT FROM AUTHOR]

Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the primary causes of the epidemics of hand-foot-and-mouth disease (HFMD) that affect more than a million children in China each year and lead to hundreds of deaths. Although there has been progress with vaccines for EV71, the development of a CVA16 vaccine has proved more challenging, and the EV71 vaccine does not give useful cross-protection, despite the capsid proteins of the two viruses sharing about 80% sequence identity. The structural details of the expanded forms of the capsids, which possess nonnative antigenicity, are now well understood, but high resolution information for the native antigenic form of CVA16 has been missing. Here, we remedy this with high resolution X-ray structures of both mature and natural empty CVA16 particles and also of empty recombinant viruslike particles of CVA16 produced in insect cells, a potential vaccine antigen. All three structures are unexpanded native particles and antigenically identical. The recombinant particles have recruited a lipid moiety to stabilize the native antigenic state that is different from the one used in a natural virus infection. As expected, the mature CVA16 virus is similar to EV71; however, structural and immunogenic comparisons highlight differences that may have implications for vaccine production. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1α (HIF-1α) is key in tumor progression and aggressiveness as it regulates a series of genes involved in angiogenesis and anaerobic metabolism. Previous studies have shown that the transcriptional levels of HIF-1α may be downregulated by endostatin. However, the molecular mechanism by which endostatin represses HIF-1α expression remains unknown. The current study investigated the mechanism by which nuclear-translocated endostatin suppresses HIF-1α activation by disrupting Zn(II) homeostasis. Endostatin was observed to downregulate HIF-1α expression at mRNA and protein levels. Blockage of endostatin nuclear translocation by RNA interference of importin α1/β1 or ectopic expression of NLS-deficient mutant nucleolin in human umbilical vein endothelial cells co-transfected with small interfering (si)-nucleolin siRNA compromises endostatin-reduced HIF-1α expression. Nuclear-translocated apo-endostatin, but not holo-endostatin, significantly disrupts the interaction between CBP/p300 and HIF-1α by disturbing Zn(II) homeostasis, which leads to the transcriptional inactivation of HIF-1α. The results reveal mechanistic insights into the method by which nuclear-translocated endostatin downregulates HIF-1α activation and provides a novel way to investigate the function of endostatin in endothelial cells. [ABSTRACT FROM AUTHOR]

CD40L, a key regulator of the immune system, was studied as both a targeting ligand and a molecular adjuvant in nucleoprotein (NP)-based host defense against influenza in mouse models with different genetic backgrounds. Adenoviral vectors secreting NP-CD40L fusion protein (denoted as rAd-SNP40L) afforded full protection of immunocompetent and immunocompromised mice (CD40L-/- and CD4-/-) against lethal influenza infection. Mechanistically, rAd-SNP40L preferentially induced early and persistent B cell germinal center formation, and accelerated Ig isotype-switching and Th1-skewed, NP-specific Ab response. Moreover, it drastically augmented primary and memory NP-specific CTL activity and polyfunctional CD8+ T cells. The markedly enhanced nonneutralizing Abs and CTLs significantly reduced viral burdens in the lungs of mice upon lethal virus challenge. Data generated from CD40L-/- and CD4-/- mice revealed that the protection was indeed CD40L mediated but CD4+ T cell independent, demonstrating the viability of the fusion Ags in protecting immunodeficient hosts. Notably, a single dose of rAd-SNP40L completely protected mice from lethal viral challenge 4 mo after immunization, representing the first report, to our knowledge, on NP in conjunction with a molecular adjuvant inducing a robust and long-lasting memory immune response against influenza. This platform is characterized by an increased in vivo load of CD40-targeted Ag upon the secretion of the fusion protein from adenovirus-infected cells and may represent a promising strategy to enhance the breadth, durability, and potency of Ag-specific immune responses. [ABSTRACT FROM AUTHOR]

Objective A recombinant antitumor/antiviral protein (Novaferon, Nova) is a new type of interferon, which is produced by artificial design technology combining DNA-shuffling and High Throughput Screening (HTS). Methods The in vitro biological activities, such as anti-tumor activity and antiviral activity of Nova and recombinant human interferon alpha-2b (rhIFN-α2b) was performed; in vivo anti-tumor activity in nude mice was also tested. Flow cytometry, histo-pathological analysis including HE staining and immunohistochemistry, and surface plasmon resonance assay were performed to investigate the underlying mechanisms analysis. Results Nova exhibited stronger anti-cancer effects compared to rhIFN-α2b in vitro and in vivo. The antitumor mechanisms of Nova may be related to S phase arrest, pro-apoptosis, and inhibition of tumor angiogenesis. Moreover, Nova exhibited a higher binding affinity for IFN receptor 2 (IFNR2) than rhIFN-α2b, which is one of the possible reasons accounting for its stronger actions against tumor cells compared with rhIFN-α2b. Conclusion Nova has strong antitumor activity and could be a potentially effective therapeutic drug for cancer. [ABSTRACT FROM AUTHOR]

Five new 2(5H)-furanone-type derivatives, pestalafuranones F-J (compounds 3-7), together with two known compounds, pestalafuranones A (1) and B (2), were isolated from the ethyl acetate extract from the fermentation broth of the endophytic fungus Nigrospora sp. BM-2 in a hypersaline medium. The structures of these metabolites were elucidated by EIMS, HREIMS and NMR spectroscopic data. Compounds 1-7 exhibited no cytotoxic activities against the MDA-MB-231 and Caski cancer cell lines. [ABSTRACT FROM AUTHOR]

The only universally conserved sequence among all influenza A viral neuraminidases is located between amino acids 222 and 230. However, the potential roles of these amino acids remain largely unknown. Through an array of experimental approaches including mutagenesis, reverse genetics, and growth kinetics, we found that this sequence could markedly affect viral replication. Additional experiments revealed that enzymes with mutations in this region demonstrated substantially decreased catalytic activity, substrate binding, and thermostability. Consistent with viral replication analyses and enzymatic studies, protein modeling suggests that these amino acids could either directly bind to the substrate or contribute to the formation of the active site in the enzyme. Collectively, these findings reveal the essential role of this unique region in enzyme function and viral growth, which provides the basis for evaluating the validity of this sequence as a potential target for antiviral intervention and vaccine development. [ABSTRACT FROM AUTHOR]

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments. Methods: Proteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM. Results: Treatment with 0.5-1 μM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10- 20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells. Conclusion: The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs. [ABSTRACT FROM AUTHOR]

Background: Recombinant human brain natriuretic peptide (rhBNP) is an important peptide-based therapeutic drug indicated for the treatment of acute heart failure. Accurate determination of the potency of therapeutic rhBNP is crucial for the safety and efficacy of the drug. The current bioassay involves use of rabbit aortic strips, with experiments being complicated and time-consuming and markedly variable in results. Animal-less methods with better precision and accuracy should be explored. We have therefore developed an alternative cell-based assay, which relies on the ability of BNP to induce cGMP production in HEK293 cells expressing BNP receptor guanylyl cyclase-A. Methodology/Principal Findings: An alternative assay based on the measurement of BNP-induced cGMP production was developed. Specifically, the bioassay employs cells engineered to express BNP receptor guanylyl cyclase-A (GCA). Upon rhBNP stimulation, the levels of the second messager cGMP in these cells drastically increased and subsequently secreted into culture supernatants. The quantity of cGMP, which corresponds to the rhBNP activity, was determined using a competitive ELISA developed by us. Compared with the traditional assay, the novel cell-based assay demonstrated better reproducibility and precision. Conclusion/Significance: The optimized cell-based assay is much simpler, more rapid and precise compared with the traditional assay using animal tissues. To our knowledge, this is the first report on a novel and viable alternative assay for rhBNP potency analysis. [ABSTRACT FROM AUTHOR]

Background: Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD). Three inactivated EV71 whole-virus vaccines of different strains developed by different manufacturers in mainland China have recently entered clinical trials. Although several studies on these vaccines have been published, a study directly comparing the immunogenicity and protective effects among them has not been carried out, which makes evaluating their relative effectiveness difficult. Thus, properly comparing newly developed vaccines has become a priority, especially in China. Methods and Findings: This comparative immunogenicity study was carried out on vaccine strains (both live and inactivated), final container products (FCPs) without adjuvant, and corresponding FCPs containing adjuvant (FCP-As) produced by three manufacturers. These vaccines were evaluated by neutralizing antibody (NAb) responses induced by the same or different dosages at one or multiple time points post-immunization. The protective efficacy of the three vaccines was also determined in one-day-old ICR mice born to immunized female mice. Survival rates were observed in these suckling mice after challenge with 20 LD50 of EV71/048M3C2. Three FCP-As, in a dose of 200 U, generated nearly 100% NAb positivity rates and similar geometric mean titers (GMTs), especially at 14--21 days post-inoculation. However, the dynamic NAb responses were different among three vaccine strains or three FCPs. The FCP-As at the lowest dose used in clinical trials (162 U) showed good protective effects in suckling mice against lethal challenge (90--100% survival), while the ED50 of NAb responses and protective effects varied among three FCP-As. Conclusions: These studies establish a standard method for measuring the immunogenicity of EV71 vaccines in mice. The data generated from our mouse model study indicated a clear dose-response relationship, which is important for vaccine quality control and assessment, especially for predicting protective efficacy in humans when combined with future clinical trial results. [ABSTRACT FROM AUTHOR]

We present a ~1" (100 pc) resolution 12CO (3-2) map of the nearby intermediate-stage interacting galaxy pair NGC 4038/9 (the Antennae galaxies) obtained with the Submillimeter Array. We find that half the CO (3-2) emission originates in the overlap region where most of the tidally induced star formation had been previously found in shorter wavelength images, with the rest being centered on each of the nuclei. The gross distribution is consistent with lower resolution single-dish images, but we show for the first time the detailed distribution of the warm and dense molecular gas across this galaxy pair at resolutions comparable to the size of a typical giant molecular complex. While we find that 58% (33/57) of the spatially resolved Giant Molecular Associations (a few x 100 pc) are located in the overlap region, only ≤ 30% spatially coincides with the optically detected star clusters, suggesting that the bulk of the CO (3-2) emission traces the regions with very recent or near future star formation activity. The spatial distribution of the CO (3-2)/CO (1-0) integrated brightness temperature ratios mainly ranges between 0.3 and 0.6, which suggests that on average the CO (3-2) line in the Antennae is not completely thermalized and similar to the average values of nearby spirals. A higher ratio is seen in both nuclei and the southern complexes in the overlap region. A higher radiation field associated with intense star formation can account tbr the nucleus of NGC 4038 and the overlap region, but the nuclear region of NGC 4039 shows relatively little star formation or active galactic nucleus activity and cannot be easily explained. We show kinematical evidence that the high line ratio in NGC 4039 is possibly caused by gas inflow into the counter-rotating central disk. [ABSTRACT FROM AUTHOR]

The traditional antiviral assays for the determination of interferon potency are reported to have considerable variability between andwithin assays. Although several reporter gene assays based on interferon-inducible promoter activities have been reported, data from comprehensive validation studies are lacking and few studies have been conducted to analyze the variant forms of interferons, which could have undesirable clinical implications. Here, a reporter gene assay employing a HEK293 cell line stably transfected with luciferase gene under the control of interferon-stimulated response element promoter was developed and validated. The assay was found to be more sensitive, with a larger detection range than the antiviral assay. Several cytokines tested did not interfere with the test, suggesting the assay possesses a certain degree of selectivity. Moreover, the robustness of the assay was demonstrated by minimal variations in the results generated by different analysts and cell passage number (up to 52 passages). Finally, the method was employed to analyze several interferon variants (interferon-α 2a) and we found that the aggregated form has completely lost its potency; while a modest loss of bioactivity in oxidized interferon was observed (approx. 23%), the deamidated form essentially retained its activity. [ABSTRACT FROM AUTHOR]

Whole-cell pertussis vaccine was introduced in China in the early 1960s. We used standard typing methods to compare 96 Bordetella pertussis isolates collected before and after introduction of vaccination, during 1953-2005. The following vaccine-type alleles of the pertussis toxin (ptx) gene were characteristic for all prevaccination strains: ptxA2, ptxA3, and ptxA4. The shift to ptxA1 occurred since 1963. All isolates collected since 1983 contained ptxA1. Pertactin (prn) allele 1, prn1, was predominant, although prn2 and prn3 have been detected since 2000. Serotypes fimbriae (Fim) 2 and Fim2,3 were found in all isolates collected before 1986. During 1997-2005, Fim3 became prevalent. Although changes in electrophoresis profiles over time were observed, the predominant profiles during 1997-2005 resembled those during the prevaccine era and those found in Europe before the 1990s. B. pertussis strains in China may differ from those in countries that have a long history of high vaccine coverage. [ABSTRACT FROM AUTHOR]

Tumor growth and metastasis depend critically on blood vessel formation. Antiangiogenesis, therefore, represents a promising strategy for cancer therapy. The kringle 5 (K5) domain of human plasminogen is a potent angiogenesis inhibitor. To investigate whether intramuscular electroporation (EP) of K5 has antitumor activity in mouse tumor models, we constructed a plasmid encoding K5 (pVAX1-K5). Hela cells transfected with this plasmid produced and secreted K5 that inhibited the migration of human microvascular endothelial cells. Intramuscular EP treatment of pVAX1-K5 inhibited the growth of Lewis lung carcinoma and prolonged the survival time of tumor-bearing mice. Angiogenesis was obviously inhibited, and apoptosis was induced in tumor cells of mice that received intramuscular EP of pVAX1-K5. On the contrary, intramuscular injection of pVAX1-K5 without EP failed to show the same effects. The data indicate that intramuscular EP of plasmid DNA encoding the K5 domain is an effective strategy for the experimental treatment of cancer by expressing K5. [ABSTRACT FROM AUTHOR]

We present Submillimeter Array observations of seven massive molecular clumps that are dark in the far-infrared for wavelengths up to 70 μm. Our 1.3 mm continuum images reveal 44 dense cores, with gas masses ranging from 1.4 to 77.1 M⊙. Twenty-nine dense cores have masses greater than 8 M⊙ and the other 15 dense cores have masses between 1.4 and 7.5 M⊙. Assuming the core density follows a power law in radius ρ ∝ r−b, the index b is found to be between 0.6 and 2.1, with a mean value of 1.3. The virial analysis reveals that the dense cores are not in virial equilibrium. CO outflow emission was detected toward six out of seven molecular clumps and associated with 17 dense cores. For five of these cores, CO emissions appear to have line wings at velocities of greater than 30 km s−1 with respect to the source systemic velocity, which indicates that most of the clumps harbor protostars and thus are not quiescent in star formation. The estimated outflow timescale increases with core mass, which likely indicates that massive cores have longer accretion timescales than less massive ones. The fragmentation analysis shows that the masses of low-mass and massive cores are roughly consistent with thermal and turbulent Jeans masses, respectively. [ABSTRACT FROM AUTHOR]

We revisit the proposed extended Schmidt law, which posits that the star formation efficiency in galaxies depends on the stellar mass surface density, by investigating spatially resolved star formation rates (SFRs), gas masses, and stellar masses of star formation regions in a vast range of galactic environments, from the outer disks of dwarf galaxies, to spiral disks and to merging galaxies, as well as individual molecular clouds in M33. We find that these regions are distributed in a tight power law as ∝ , which is also valid for the integrated measurements of disk and merging galaxies at high-z. Interestingly, we show that star formation regions in the outer disks of dwarf galaxies with down to 10−5 yr−1 kpc−2, which are outliers of both the Kennicutt–Schmidt and Silk–Elmegreen laws, also follow the extended Schmidt law. Other outliers in the Kennicutt–Schmidt law, such as extremely metal-poor star formation regions, also show significantly reduced deviation from the extended Schmidt law. These results suggest an important role for existing stars in helping to regulate star formation through the effect of their gravity on the midplane pressure in a wide range of galactic environments. [ABSTRACT FROM AUTHOR]

We present 2.5-square-degree C2H N = 1–0 and N2H+J = 1–0 maps of the ρ Ophiuchi molecular cloud complex. These are the first large-scale maps of the ρ Ophiuchi molecular cloud complex with these two tracers. The C2H emission is spatially more extended than the N2H+ emission. One faint N2H+ clump, Oph-M, and one C2H ring, Oph-RingSW, are identified for the first time. The observed C2H-to-N2H+ abundance ratio ([C2H]/[N2H+]) varies between 5 and 110. We modeled the C2H and N2H+ abundances with 1D chemical models, which show a clear decline of [C2H]/[N2H+] with chemical age. Such an evolutionary trend is little affected by temperatures when they are below 40 K. At high density (nH > 105 cm−3), however, the time it takes for the abundance ratio to drop at least one order of magnitude becomes less than the dynamical time (e.g., turbulence crossing time of ∼105 yr). The observed [C2H]/[N2H+] difference between L1688 and L1689 can be explained by L1688 having chemically younger gas in relatively less dense regions. The observed [C2H]/[N2H+] values are the results of time evolution, accelerated at higher densities. For the relatively low density regions in L1688 where only C2H emission was detected, the gas should be chemically younger. [ABSTRACT FROM AUTHOR]

Bordetella pertussis is the causative agent of pertussis. Here, we report the genome sequence of Bordetella pertussis strain CS, isolated from an infant patient in Beijing and widely used as a vaccine strain for production of an acellular pertussis vaccine in China. [ABSTRACT FROM AUTHOR]