Highlights • NRG1 protects against OGD-induced cortical neuronal apoptosis. • NRG1-mediated neuroprotection is blocked by neutralizing NRG1 and ErbB4 inhibition. • GABA receptor agonists have no ...synergistic effect with NRG1. • NRG1-mediated neuroprotection is partly blocked by GABA receptor antagonists. • The NRG1 neuroprotection against brain ischemia is abolished in PV-ErbB4−/− mice.
The biosynthesis of many polysaccharides, including bacterial peptidoglycan and eukaryotic N-linked glycans, requires transport of lipid-linked oligosaccharide (LLO) precursors across the membrane by ...specialized flippases. MurJ is the flippase for the lipid-linked peptidoglycan precursor Lipid II, a key player in bacterial cell wall synthesis, and a target of recently discovered antibacterials. However, the flipping mechanism of LLOs including Lipid II remains poorly understood due to a dearth of structural information. Here we report crystal structures of MurJ captured in inward-closed, inward-open, inward-occluded and outward-facing conformations. Together with mutagenesis studies, we elucidate the conformational transitions in MurJ that mediate lipid flipping, identify the key ion for function, and provide a framework for the development of inhibitors.
The enumeration and characterization of circulating tumor cells (CTCs), found in the peripheral blood of cancer patients, provide a potentially accessible source for cancer diagnosis and prognosis. ...This work reports on a novel spiral microfluidic device with a trapezoidal cross-section for ultra-fast, label-free enrichment of CTCs from clinically relevant blood volumes. The technique utilizes the inherent Dean vortex flows present in curvilinear microchannels under continuous flow, along with inertial lift forces which focus larger CTCs against the inner wall. Using a trapezoidal cross-section as opposed to a traditional rectangular cross-section, the position of the Dean vortex core can be altered to achieve separation. Smaller hematologic components are trapped in the Dean vortices skewed towards the outer channel walls and eventually removed at the outer outlet, while the larger CTCs equilibrate near the inner channel wall and are collected from the inner outlet. By using a single spiral microchannel with one inlet and two outlets, we have successfully isolated and recovered more than 80% of the tested cancer cell line cells (MCF-7, T24 and MDA-MB-231) spiked in 7.5 mL of blood within 8 min with extremely high purity (400-680 WBCs mL(-1); ~4 log depletion of WBCs). Putative CTCs were detected and isolated from 100% of the patient samples (n = 10) with advanced stage metastatic breast and lung cancer using standard biomarkers (CK, CD45 and DAPI) with the frequencies ranging from 3-125 CTCs mL(-1). We expect this simple and elegant approach can surmount the shortcomings of traditional affinity-based CTC isolation techniques as well as enable fundamental studies on CTCs to guide treatment and enhance patient care.
Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the ...esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members.
Fatal human respiratory disease associated with influenza A subtype H5N1 has been documented in Hong Kong, and more recently in Vietnam, Thailand and Cambodia. We previously demonstrated that ...patients with H5N1 disease had unusually high serum levels of IP-10 (interferon-gamma-inducible protein-10). Furthermore, when compared with human influenza virus subtype H1N1, the H5N1 viruses in 1997 (A/Hong Kong/483/97) (H5N1/97) were more potent inducers of pro-inflammatory cytokines (e.g. tumor necrosis factor-a) and chemokines (e.g. IP-10) from primary human macrophages in vitro, which suggests that cytokines dysregulation may play a role in pathogenesis of H5N1 disease. Since respiratory epithelial cells are the primary target cell for replication of influenza viruses, it is pertinent to investigate the cytokine induction profile of H5N1 viruses in these cells.
We used quantitative RT-PCR and ELISA to compare the profile of cytokine and chemokine gene expression induced by H5N1 viruses A/HK/483/97 (H5N1/97), A/Vietnam/1194/04 and A/Vietnam/3046/04 (both H5N1/04) with that of human H1N1 virus in human primary alveolar and bronchial epithelial cells in vitro.
We demonstrated that in comparison to human H1N1 viruses, H5N1/97 and H5N1/04 viruses were more potent inducers of IP-10, interferon beta, RANTES (regulated on activation, normal T cell expressed and secreted) and interleukin 6 (IL-6) in primary human alveolar and bronchial epithelial cells in vitro. Recent H5N1 viruses from Vietnam (H5N1/04) appeared to be even more potent at inducing IP-10 than H5N1/97 virus.
The H5N1/97 and H5N1/04 subtype influenza A viruses are more potent inducers of proinflammatory cytokines and chemokines in primary human respiratory epithelial cells than subtype H1N1 virus. We suggest that this hyper-induction of cytokines may be relevant to the pathogenesis of human H5N1 disease.
A
bstract
Using
e
+
e
−
collision data corresponding to a total integrated luminosity of 12.9 fb
−
1
collected with the BESIII detector at the BEPCII collider, the exclusive Born cross sections and ...the effective form factors of the reaction
e
+
e
−
→
Ξ
−
Ξ
¯
+
are measured via the single baryon-tag method at 23 center-of-mass energies between 3.510 and 4.843 GeV. Evidence for the decay
ψ
3770
→
Ξ
−
Ξ
¯
+
is observed with a significance of 4.5
σ
by analyzing the measured cross sections together with earlier BESIII results. For the other charmonium(-like) states
ψ
(4040),
ψ
(4160),
Y
(4230),
Y
(4360),
ψ
(4415), and
Y
(4660), no significant signal of their decay to
Ξ
−
Ξ
¯
+
is found. For these states, upper limits of the products of the branching fraction and the electronic partial width at the 90% confidence level are provided.
•The microstructure evolution of a hot deformed Ti-55511 alloy is studied.•A unified constitutive equation is established to model the flow behaviors and microstructure evolution.•The discontinues ...and geometric DRX mechanisms are dominant.•Increasing the deformation temperature can increase the DRX fraction and sub-grain size.•The chain-like small DRX grains and the flow location occur at high strain rates.
The microstructure evolution of a Ti-55511 alloy deformed at high temperatures (from 1163 K to 1253 K) and wide strain rate range (from 10 s−1 to 0.001 s−1) is studied by isothermal compression tests. Based on the sensitivity of dislocation density to deformation conditions, a unified constitutive equation is established to describe the evolution of flow stress, grain size and dynamic recrystallization (DRX) fraction. The results show that the initial grain boundaries are serrated, and the sub-grains and DRX grains are formed with the further deformation. Furthermore, the discontinuous and geometric DRX mechanisms are dominant recrystallization mechanism. Increasing the deformation temperature can increase the DRX fraction and sub-grain size. However, the abnormal growth of β grains occurs at 1253 K. The DRX fraction decreases with the increased strain rate. Meanwhile, the chain-like small DRX grains and the flow localization occur at high strain rates. Also, the established constitutive model is verified by the experimental results, and the correlation coefficient is 0.9929, indicating the excellent prediction ability of the established constitutive model.
H5N1 Influenza: A Protean Pandemic Threat Guan, Y.; Poon, L. L. M.; Cheung, C. Y. ...
Proceedings of the National Academy of Sciences - PNAS,
05/2004, Letnik:
101, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Infection with avian influenza A virus of the H5N1 subtype (isolates A/HK/212/03 and A/HK/213/03) was fatal to one of two members of a family in southern China in 2003. This incident was preceded by ...lethal outbreaks of H5N1 influenza in waterfowl, which are the natural hosts of these viruses and, therefore, normally have asymptomatic infection. The hemagglutinin genes of the A/HK/212/03-like viruses isolated from humans and waterfowl share the lineage of the H5N1 viruses that caused the first known cases of human disease in Hong Kong in 1997, but their internal protein genes originated elsewhere. The hemagglutinin of the recent human isolates has undergone significant antigenic drift. Like the 1997 human H5N1 isolates, the 2003 human H5N1 isolates induced the overproduction of proinflammatory cytokines by primary human macrophages in vitro, whereas the precursor H5N1 viruses and other H5N1 reassortants isolated in 2001 did not. The acquisition by the viruses of characteristics that enhance virulence in humans and waterfowl and their potential for wider distribution by infected migrating birds are causes for renewed pandemic concern.
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