Distinct roles of NMB and GRP in itch transmission

A key question in our understanding of itch coding mechanisms is whether itch is relayed by dedicated molecular and neuronal pathways. Previous studies suggested that gastrin-releasing peptide (GRP) is an itch-specific neurotransmitter. Neuromedin B (NMB) is a mammalian member of the bombesin family of peptides closely related to GRP, but its role in itch is unclear. Here, we show that itch deficits in mice lacking NMB or GRP are non-redundant and Nmb/Grp double KO (DKO) mice displayed additive deficits. Furthermore, both Nmb/Grp and Nmbr/Grpr DKO mice responded normally to a wide array of noxious stimuli. Ablation of NMBR neurons partially attenuated peripherally induced itch without compromising nociceptive processing. Importantly, electrophysiological studies suggested that GRPR neurons receive glutamatergic input from NMBR neurons. Thus, we propose that NMB and GRP may transmit discrete itch information and NMBR neurons are an integral part of neural circuits for itch in the spinal cord

Diagnosis of pulmonary tuberculosis among asymptomatic HIV+ patients in Guangxi, China

BACKGROUND: Pulmonary tuberculosis (PTB) among asymptomatic Chinese patients with HIV infection has not been investigated despite high tuberculosis burden in China. This study was aimed to evaluate the prevalence, risk factors and clinical outcomes of PTB among asymptomatic patients with HIV/AIDS in Guangxi to facilitate the development of diagnostic and treatment strategies. METHODS: All asymptomatic adult HIV-infected patients with CD4 < 350 cells/µl who attended four HIV clinics in Guangxi between August 2006 and March 2008 were evaluated for active PTB with physical examination, chest X-ray (CXR), sputum smear and/or sputum liquid culture. Data were described using median (interquartile range, IQR) and frequencies. Univariate and multivariate Logistic regression analyses were performed to identify risk factors associated with PTB. RESULTS: Among 340 asymptomatic subjects, 15 (4%) were diagnosed with PTB, with 4 (27%) sputum smear positive and 8 (53%) sputum culture positive. CXR has higher diagnostic sensitivity (87%) than sputum smear (25%) and sputum culture (67%), but lower specificity (56%) compared with sputum smear (99%) and culture (100%). In univariate analysis, injection drug user, body mass index (BMI) < 18 kg/m(2), CD4 < 50 cells/µl and presence of peripheral lymphadenopathy were associated with an increased risk of asymptomatic PTB, while in multivariate analysis only peripheral lymphadenopathy maintained statistical significance (OR = 7.6, 95%CI 1.4 - 40). Patients with negative smear and minor or no abnormalities on CXR had longer interval between screening and TB treatment. CONCLUSIONS: PTB was relatively common in this group of HIV(+) asymptomatic Chinese patients. Diagnosis is challenging especially where sputum culture is unavailable. These findings suggest that an enhanced evaluation for PTB needs to be integrated with HIV care in China and transmission prevention in China to control at both households and health care facilities, especially for patients with factors associated with a higher risk of PTB

Comparison of the Efficacy of Intravitreal Aflibercept and Bevacizumab for Macular Edema Secondary to Branch Retinal Vein Occlusion

Fifty-two eyes of 52 patients with treatment-naïve macular edema associated with perfused branch retinal vein occlusion were retrospectively reviewed. Twenty-seven cases received PRN intravitreal bevacizumab, and 25 cases were treated by PRN intravitreal aflibercept with monthly follow-ups for 12 months. Both aflibercept and bevacizumab were effective in reduction of macular thickness and improvement of visual acuity for the participants. Both antivascular endothelial growth factor agents had similar efficacy and duration of treatment for these eyes with macular edema secondary to branch retinal vein occlusion during a 12-month period. No serious systemic or ocular adverse events were reported

The H3K36me2 writer-reader dependency in H3K27M-DIPG

Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG

Neutral Kaon Interferometry in Au+Au collisions at sqrt(s_NN) = 200 GeV

We present the first statistically meaningful results from two-K0s interferometry in heavy-ion collisions. A model that takes the effect of the strong interaction into account has been used to fit the measured correlation function. The effects of single and coupled channel were explored. At the mean transverse mass m_T = 1.07 GeV, we obtain the values R = 4.09 +/- 0.46 (stat.) +/- 0.31 (sys) fm and lambda = 0.92 +/- 0.23 (stat) +/- 0.13 (sys), where R and lambda are the invariant radius and chaoticity parameters respectively. The results are qualitatively consistent with m_T systematics established with pions in a scenario characterized by a strong collective flow.Comment: 11 pages, 10 figure

Small-Molecule Synthetic Compound Norcantharidin Reverses Multi-Drug Resistance by Regulating Sonic Hedgehog Signaling in Human Breast Cancer Cells

Multi-drug resistance (MDR), an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC) transporters and activated Sonic hedgehog (Shh) signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX), we examined the effect and mechanism of norcantharidin (NCTD), a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S) and DOX-resistant (MCF-7R) cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells

Identified baryon and meson distributions at large transverse momenta from Au+Au collisions at sNN=200\sqrt{s_{_{NN}}} = 200 GeV

Transverse momentum spectra of $\pi^{\pm}$, $p$ and $\bar{p}$ up to 12 GeV/c at mid-rapidity in centrality selected Au+Au collisions at $\sqrt{s_{_{NN}}} = 200$ GeV are presented. In central Au+Au collisions, both $\pi^{\pm}$ and $p(\bar{p})$ show significant suppression with respect to binary scaling at $p_T >$ 4 GeV/c. Protons and anti-protons are less suppressed than $\pi^{\pm}$, in the range 1.5 $< p_{T} <$6 GeV/c. The $\pi^-/\pi^+$ and $\bar{p}/p$ ratios show at most a weak $p_T$ dependence and no significant centrality dependence. The $p/\pi$ ratios in central Au+Au collisions approach the values in p+p and d+Au collisions at $p_T >$ 5 GeV/c. The results at high $p_T$ indicate that the partonic sources of $\pi^{\pm}$, $p$ and $\bar{p}$ have similar energy loss when traversing the nuclear medium.Comment: 6 pages, 4 figure

Longitudinal double-spin asymmetry and cross section for inclusive jet production in polarized proton collisions at sqrt(s) = 200 GeV

We report a measurement of the longitudinal double-spin asymmetry A_LL and the differential cross section for inclusive midrapidity jet production in polarized proton collisions at sqrt(s)=200 GeV. The cross section data cover transverse momenta 5 < pT < 50 GeV/c and agree with next-to-leading order perturbative QCD evaluations. The A_LL data cover 5 < pT < 17 GeV/c and disfavor at 98% C.L. maximal positive gluon polarization in the polarized nucleon.Comment: 6 pages, 3 figures. Minor changes from review process in Phys. Rev. Lett. Plain text tables of data in STAR publications may be found at http://www.star.bnl.gov/central/publications

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity

Minijet deformation and charge-independent angular correlations on momentum subspace (η,ϕ)(\eta,\phi) in Au-Au collisions at sNN\sqrt{s_{NN}} = 130 GeV

First measurements of charge-independent correlations on angular difference variables $\eta_1 - \eta_2$ (pseudorapidity) and $\phi_1 - \phi_2$ (azimuth) are presented for primary charged hadrons with transverse momentum $0.15 \leq p_t \leq 2$ GeV/$c$ and $|\eta| \leq 1.3$ from Au-Au collisions at $\sqrt{s_{NN}} = 130$ GeV. Strong charge-independent angular correlations are observed associated with jet-like structures and elliptic flow. The width of the jet-like peak on $\eta_1 - \eta_2$ increases by a factor 2.3 from peripheral to central collisions, suggesting strong coupling of semi-hard scattered partons to a longitudinally-expanding medium. New methods of jet analysis introduced here provide evidence for nonperturbative QCD medium effects in heavy ion collisions.Comment: 8 pages, 4 figure