From human Megakaryocytes to platelets: Effects of aspirin on high-mobility group Box 1/receptor for advanced glycation end products axis

Platelets (PLTs) are the major source of high-mobility group box 1 (HMGB1), a protein that is involved in sterile inflammation of blood vessels and thrombosis. Megakaryocytes (MKs) synthesize HMGB1 and transfer both protein and mRNA into PLTs and PLT-derived microvesicles (MV). Free HMGB1 found in supernatants of in vitro differentiated MKs and in a megakaryoblastic cell line (DAMI cells). Aspirin “in vivo” and “in vitro” not only reduces HMGB1 and receptor for advanced glycation end products expression on MKs and PLTs but also drives the movement of HMGB1 from MKs into PLTs and PLT-derived MV. These findings suggest that consumption of low doses of aspirin reduces the risk of atherosclerosis complications as well as reducing PLT aggregation by the inhibition of COX-1

p140Cap regulates memory and synaptic plasticity through Src-mediated and citron-N-mediated actin reorganization.

Abstract A major challenge in the neuroscience field is the identification of molecules and pathways that control synaptic plasticity and memory. Dendritic spines play a pivotal role in these processes, as the major sites of excitatory synapses in neuronal communication. Previous studies have shown that the scaffold protein p140Cap localizes into dendritic spines and that its knockdown negatively modulates spine shape in culture. However, so far, there is no information on its in vivo relevance. By using a knock-outmousemodel, we here demonstrate that p140Cap is a key element for both learning and synaptic plasticity. Indeed, p140Cap(-/-) mice are impaired in object recognition test, as well as in LTP and in LTD measurements. The in vivo effects of p140Cap loss are presumably attenuated by noncell-autonomous events, since primary neurons obtained from p140Cap(-/-) mice show a strong reduction in number of mushroom spines and abnormal organization of synapse-associated F-actin. These phenotypes are most likely caused by a local reduction of the inhibitory control of RhoA and of cortactin toward the actin-depolymerizing factor cofilin. These events can be controlled by p140Cap through its capability to directly inhibit the activation of Src kinase and by its binding to the scaffold protein Citron-N. Altogether, our results provide new insight into how protein associated with dynamic microtubules may regulate spine actin organization through interaction with postsynaptic density components

Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms

With the intent of dissecting the molecular complexity of Philadelphia-negative myeloproliferative neoplasms (MPN), we designed a target enrichment panel to explore, using next-generation sequencing (NGS), the mutational status of an extensive list of 2,000 cancer-associated genes and microRNAs. The genomic DNA of granulocytes and in-vitro-expanded CD3+ T-lymphocytes, as a germline control, was target-enriched and sequenced in a learning cohort of 20 MPN patients using Roche 454 technology. We identified 141 genuine somatic mutations, most of which were not previously described. To test the frequency of the identified variants, a larger validation cohort of 189 MPN patients was additionally screened for these mutations using Ion Torrent AmpliSeq NGS. Excluding the genes already described in MPN, for 8 genes (SCRIB, MIR662, BARD1, TCF12, FAT4, DAP3, POLG, and NRAS), we demonstrated a mutation frequency between 3 and 8%. We also found that mutations at codon 12 of NRAS (NRASG12V and NRASG12D) were significantly associated, for primary myelofibrosis (PMF), with highest DIPSS-plus score categories. This association was then confirmed in 66 additional PMF patients composing a final dataset of 168 PMF showing an NRAS mutation frequency of 4.7%, which was associated with a worse outcome, as defined by the DIPSS plus score

Confirmation of a charged charmoniumlike state Zc(3885)∓Z_c(3885)^{\mp} in e+e−→π±(DDˉ∗)∓e^+e^-\to\pi^{\pm}(D\bar{D}^*)^\mp with double DD tag

We present a study of the process $e^+e^-\to\pi^{\pm}(D\bar{D}^*)^{\mp}$ using data samples of 1092~pb$^{-1}$ at $\sqrt{s}=4.23$~GeV and 826~pb$^{-1}$ at $\sqrt{s}=4.26$~GeV collected with the BESIII detector at the BEPCII storage ring. With full reconstruction of the $D$ meson pair and the bachelor $\pi^{\pm}$ in the final state, we confirm the existence of the charged structure $Z_c(3885)^{\mp}$ in the $(D\bar{D}^*)^{\mp}$ system in the two isospin processes $e^+e^-\to\pi^+D^0D^{*-}$ and $e^+e^-\to\pi^+D^-D^{*0}$. By performing a simultaneous fit, the statistical significance of $Zc(3885)^{\mp}$ signal is determined to be greater than 10$\sigma$, and its pole mass and width are measured to be $M_{\rm{pole}}$=(3881.7$\pm$1.6(stat.)$\pm$1.6(syst.))~MeV/$c^2$ and $\Gamma_{\rm{pole}}$=(26.6$\pm$2.0(stat.)$\pm$2.1(syst.))~MeV, respectively. The Born cross section times the $(D\bar{D}^*)^{\mp}$ branching fraction ($\sigma(e^+e^-\to\pi^{\pm}Z_{c}(3885)^{\mp}) \times Br(Z_{c}(3885)^{\mp}\to(D\bar{D}^*)^{\mp})$) is measured to be $(141.6\pm7.9(\text{stat.})\pm12.3(\text{syst.}))~\text{pb}$ at $\sqrt{s}=4.23$~GeV and $(108.4\pm6.9(\text{stat.})\pm8.8(\text{syst.}))~\text{pb}$ at $\sqrt{s}=4.26$~GeV. The polar angular distribution of the $\pi^{\pm}$-$Z_c(3885)^{\mp}$ system is consistent with the expectation of a quantum number assignment of $J^P=1^+$ for $Z_c(3885)^{\mp}$

Measurement of the proton form factor by studying e+e−→ppˉe^{+} e^{-}\rightarrow p\bar{p}

Using data samples collected with the BESIII detector at the BEPCII collider, we measure the Born cross section of $e^{+}e^{-}\rightarrow p\bar{p}$ at 12 center-of-mass energies from 2232.4 to 3671.0 MeV. The corresponding effective electromagnetic form factor of the proton is deduced under the assumption that the electric and magnetic form factors are equal $(|G_{E}|= |G_{M}|)$. In addition, the ratio of electric to magnetic form factors, $|G_{E}/G_{M}|$, and $|G_{M}|$ are extracted by fitting the polar angle distribution of the proton for the data samples with larger statistics, namely at $\sqrt{s}=$ 2232.4 and 2400.0 MeV and a combined sample at $\sqrt{s}$ = 3050.0, 3060.0 and 3080.0 MeV, respectively. The measured cross sections are in agreement with recent results from BaBar, improving the overall uncertainty by about 30\%. The $|G_{E}/G_{M}|$ ratios are close to unity and consistent with BaBar results in the same $q^{2}$ region, which indicates the data are consistent with the assumption that $|G_{E}|=|G_{M}|$ within uncertainties.Comment: 13 pages, 24 figure

An amplitude analysis of the π0π0\pi^{0}\pi^{0} system produced in radiative J/ψJ/\psi decays

An amplitude analysis of the $\pi^{0}\pi^{0}$ system produced in radiative $J/\psi$ decays is presented. In particular, a piecewise function that describes the dynamics of the $\pi^{0}\pi^{0}$ system is determined as a function of $M_{\pi^{0}\pi^{0}}$ from an analysis of the $(1.311\pm0.011)\times10^{9}$ $J/\psi$ decays collected by the BESIII detector. The goal of this analysis is to provide a description of the scalar and tensor components of the $\pi^0\pi^0$ system while making minimal assumptions about the properties or number of poles in the amplitude. Such a model-independent description allows one to integrate these results with other related results from complementary reactions in the development of phenomenological models, which can then be used to directly fit experimental data to obtain parameters of interest. The branching fraction of $J/\psi \to \gamma \pi^{0}\pi^{0}$ is determined to be $(1.15\pm0.05)\times10^{-3}$, where the uncertainty is systematic only and the statistical uncertainty is negligible.Comment: Submitted to Phys. Rev. D 19 pages, 4 figure

Observation of the isospin-violating decay J/ψ→ϕπ0f0(980)J/\psi \to \phi\pi^{0}f_{0}(980)

Using a sample of 1.31 billion $J/\psi$ events collected with the BESIII detector at the BEPCII collider, the decays $J/\psi \to \phi \pi^{+}\pi^{-}\pi^{0}$ and $J/\psi \to \phi \pi^{0}\pi^{0}\pi^{0}$ are investigated. The isospin violating decay $J/\psi \to \phi \pi^{0} f_{0}(980)$ with $f_{0}(980) \to \pi\pi$, is observed for the first time. The width of the $f_{0}(980)$ obtained from the dipion mass spectrum is found to be much smaller than the world average value. In the $\pi^{0} f_{0}(980)$ mass spectrum, there is evidence of $f_1(1285)$ production. By studying the decay $J/\psi \to \phi\eta'$, the branching fractions of $\eta' \to \pi^{+}\pi^{-}\pi^{0}$ and $\eta' \to \pi^{0}\pi^{0}\pi^{0}$, as well as their ratio, are also measured.Comment: 10 pages, 10 figures, published in Phys. Rev.

Measurement of the e+e−→ηJ/ψe^{+}e^{-} \to \eta J/\psi cross section and search for e+e−→π0J/ψe^{+}e^{-} \to \pi^{0} J/\psi at center-of-mass energies between 3.810 and 4.600~GeV

Using data samples collected with the BESIII detector operating at the BEPCII collider at center-of-mass energies from 3.810 to 4.600 GeV, we perform a study of $e^{+}e^{-} \to \eta J/\psi$ and $\pi^0 J/\psi$. Statistically significant signals of $e^{+}e^{-} \to \eta J/\psi$ are observed at $\sqrt{s}$ = 4.190, 4.210, 4.220, 4.230, 4.245, 4.260, 4.360 and 4.420 GeV, while no signals of $e^{+}e^{-} \to \pi^{0} J/\psi$ are observed. The measured energy-dependent Born cross section for $e^{+}e^{-} \to \eta J/\psi$ shows an enhancement around 4.2~GeV. The measurement is compatible with an earlier measurement by Belle, but with a significantly improved precision

Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations

Objective: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. Methods: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes. Results: Fibroblasts from 3 biallelic OPA1(2/2) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)–depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA–treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts. Conclusions: We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion

Six hundred years of South American tree rings reveal an increase in severe hydroclimatic events since mid-20th century

South American (SA) societies are highly vulnerable to droughts and pluvials, but lack of long-term climate observations severely limits our understanding of the global processes driving climatic variability in the region. The number and quality of SA climate-sensitive tree ring chronologies have significantly increased in recent decades, now providing a robust network of 286 records for characterizing hydroclimate variability since 1400 CE. We combine this network with a self-calibrated Palmer Drought Severity Index (scPDSI) dataset to derive the South American Drought Atlas (SADA) over the continent south of 12°S. The gridded annual reconstruction of austral summer scPDSI is the most spatially complete estimate of SA hydroclimate to date, and well matches past historical dry/wet events. Relating the SADA to the Australia–New Zealand Drought Atlas, sea surface temperatures and atmospheric pressure fields, we determine that the El Niño–Southern Oscillation (ENSO) and the Southern Annular Mode (SAM) are strongly associated with spatially extended droughts and pluvials over the SADA domain during the past several centuries. SADA also exhibits more extended severe droughts and extreme pluvials since the mid-20th century. Extensive droughts are consistent with the observed 20th-century trend toward positive SAM anomalies concomitant with the weakening of midlatitude Westerlies, while low-level moisture transport intensified by global warming has favored extreme rainfall across the subtropics. The SADA thus provides a long-term context for observed hydroclimatic changes and for 21st-century Intergovernmental Panel on Climate Change (IPCC) projections that suggest SA will experience more frequent/severe droughts and rainfall events as a consequence of increasing greenhouse gas emissions