The authors' full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Kan at P.O. Box 249, 130 Dong-An Road, Shanghai 200032, China, or at kanh@ fudan . edu . cn.Drs. Liu and R. Chen and Drs. Gasparrini and Kan contributed equally to this article.

Atmospheric new particle formation (NPF) is an important global phenomenon that is nevertheless sensitive to ambient conditions. According to both observation and theoretical arguments, NPF usually requires a relatively high sulfuric acid (HSO) concentration to promote the formation of new particles and a low preexisting aerosol loading to minimize the sink of new particles. We investigated NPF in Shanghai and were able to observe both precursor vapors (HSO) and initial clusters at a molecular level in a megacity. High NPF rates were observed to coincide with several familiar markers suggestive of HSO-dimethylamine (DMA)-water (HO) nucleation, including sulfuric acid dimers and HSO-DMA clusters. In a cluster kinetics simulation, the observed concentration of sulfuric acid was high enough to explain the particle growth to ~3 nanometers under the very high condensation sink, whereas the subsequent higher growth rate beyond this size is believed to result from the added contribution of condensing organic species. These findings will help in understanding urban NPF and its air quality and climate effects, as well as in formulating policies to mitigate secondary particle formation in China.

Marine macroalgae Enteromorpha prolifera, one of the main algae genera for green tide, was converted to bio-oil by hydrothermal liquefaction in a batch reactor at temperatures of 220-320 °C. The liquefaction products were separated into a dichloromethane-soluble fraction (bio-oil), water-soluble fraction, solid residue, and gaseous fraction. Effects of the temperature, reaction time, and Na 2 CO 3 catalyst on the yields of liquefaction products were investigated. A moderate temperature of 300 °C with 5 wt % Na 2 CO 3 and reaction time of 30 min led to the highest bio-oil yield of 23.0 wt %. The raw algae and liquefaction products were analyzed using elemental analysis, Fourier transform infrared (FTIR) spectroscopy, gas chromatography-mass spectrometry (GC-MS), and 1 H nuclear magnetic resonance (NMR). The higher heating values (HHVs) of bio-oils obtained at 300 °C were around 28-30 MJ/kg. The bio-oil was a complex mixture of ketones, aldehydes, phenols, alkenes, fatty acids, esters, aromatics, and nitrogencontaining heterocyclic compounds. Acetic acid was the main component of the water-soluble products. The results might be helpful to find a possible strategy for use of byproducts of green tide as feedstock for bio-oil production, which should be beneficial for environmental protection and renewable energy development.

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A long-acting factor VIII (FVIII) as a replacement therapy for hemophilia A would significantly improve treatment options for patients with hemophilia A. To develop a FVIII with an extended circulating half-life, but without a reduction in activity, we have engineered 23 FVIII variants with introduced surface-exposed cysteines to which a polyethylene glycol (PEG) polymer was specifically conjugated. Screening of variant expression level, PEGylation yield, and functional assay identified several conjugates retaining full in vitro coagulation activity and von Willebrand factor (VWF) binding. PEGylated FVIII variants exhibited improved pharmacokinetics in hemophilic mice and rabbits. In addition, pharmacokinetic studies in VWF knockout mice indicated that larger molecular weight PEG may substitute for VWF in protecting PEGylated FVIII from clearance in vivo. In bleeding models of hemophilic mice, PEGylated FVIII not only exhibited prolonged efficacy that is consistent with the improved pharmacokinetics but also showed efficacy in stopping acute bleeds comparable with that of unmodified rFVIII. In summary site-specifically PEGylated FVIII has the potential to be a long-acting prophylactic treatment while being fully efficacious for on-demand treatment for patients with hemophilia A. (Blood. 2010;116(2):270-279)

Toll-like receptors (TLR) 2 and 4 are cell surface receptors that in association with CD14 enable phagocytic inflammatory responses to a variety of microbial products. Activation via these receptors triggers signaling cascades, resulting in nuclear translocation of NF-κB and a proinflammatory response including TNF-α production. We investigated whether TLRs participate in the host response to Cryptococcus neoformans glucuronoxylomannan (GXM), the major capsular polysaccharide of this fungus. Chinese hamster ovary fibroblasts transfected with human TLR2, TLR4, and/or CD14 bound fluorescently labeled GXM. The transfected Chinese hamster ovary cells were challenged with GXM, and activation of an NF-κB-dependent reporter construct was evaluated. Activation was observed in cells transfected with both CD14 and TLR4. GXM also stimulated nuclear NF-κB translocation in PBMC and RAW 264.7 cells. However, stimulation of these cells with GXM resulted in neither TNF-α secretion nor activation of the extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun N-terminal kinase mitogen-activated protein kinase pathways. These findings suggest that TLRs, in conjunction with CD14, function as pattern recognition receptors for GXM. Furthermore, whereas GXM stimulates cells to translocate NF-κB to the nucleus, it does not induce activation of mitogen-activated protein kinase pathways or release of TNF-α. Taken together, these observations suggest a novel scenario whereby GXM stimulates cells via CD14 and TLR4, resulting in an incomplete activation of pathways necessary for TNF-α production.

Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ATM-deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin as well as to MEF2A and CREB, leading to histone de-acetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts the neurodegenerative changes and rescues several behavioral abnormalities of Atm mutants. Full rescue, however, also requires HDAC4 in the cytoplasm, suggesting that the A-T phenotype results both from a loss of cytoplasmic HDAC4 and its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The HDAC4 phosphatase, PP2A, is down regulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and nuclear accumulation. Our results define a crucial role of nuclear accumulation and cytoplasmic depletion of HDAC4 in the events leading to A-T neurodegeneration.

The hallmark neuropathology of Huntington's disease (HD) is due to elongation of a polyglutamine segment in huntingtin, a novel approximately 350 kDa protein of unknown function. We used a yeast two-hybrid interactor screen to identify proteins whose association with huntingtin might be altered in the pathogenic process. Surprisingly, no interactors were found with internal and C-terminal segments of huntingtin. In contrast, huntingtin's N-terminus detected 13 distinct proteins, seven novel and six reported previously. Among these, we identified a major interactor class, comprising three distinct WW domain proteins, HYPA, HYPB and HYPC, that bind normal and mutant huntingtin in extracts of HD lymphoblastoid cells. This interaction is mediated by huntingtin's proline-rich region and is enhanced by lengthening the adjacent glutamine tract. Although HYPB and HYPC are novel, HYPA is human FBP-11, a protein implicated in spliceosome function. The emergence of this class of proteins as huntingtin partners argues that a WW domain-mediated process, such as non-receptor signaling, protein degradation or pre-mRNA splicing, may participate in HD pathogenesis.