Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation

Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state. Objective: We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism. Methods and Results: We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3-mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration. Conclusions: Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease

Immune-Complex Mimics as a Molecular Platform for Adjuvant-Free Vaccine Delivery

Protein-based vaccine development faces the difficult challenge of finding robust yet non-toxic adjuvants suitable for humans. Here, using a molecular engineering approach, we have developed a molecular platform for generating self-adjuvanting immunogens that do not depend on exogenous adjuvants for induction of immune responses. These are based on the concept of Immune Complex Mimics (ICM), structures that are formed between an oligomeric antigen and a monoclonal antibody (mAb) to that antigen. In this way, the roles of antigens and antibodies within the structure of immune complexes are reversed, so that a single monoclonal antibody, rather than polyclonal sera or expensive mAb cocktails can be used. We tested this approach in the context of Mycobacterium tuberculosis (MTB) infection by linking the highly immunogenic and potentially protective Ag85B with the oligomeric Acr (alpha crystallin, HspX) antigen. When combined with an anti-Acr monoclonal antibody, the fusion protein formed ICM which bound to C1q component of the complement system and were readily taken up by antigen-presenting cells in vitro. ICM induced a strong Th1/Th2 mixed type antibody response, which was comparable to cholera toxin adjuvanted antigen, but only moderate levels of T cell proliferation and IFN-γ secretion. Unfortunately, the systemic administration of ICM did not confer statistically significant protection against intranasal MTB challenge, although a small BCG-boosting effect was observed. We conclude that ICM are capable of inducing strong humoral responses to incorporated antigens and may be a suitable vaccination approach for pathogens other than MTB, where antibody-based immunity may play a more protective role

CDPKs CPK6 and CPK3 Function in ABA Regulation of Guard Cell S-Type Anion- and Ca(2+)- Permeable Channels and Stomatal Closure

Abscisic acid (ABA) signal transduction has been proposed to utilize cytosolic Ca(2+) in guard cell ion channel regulation. However, genetic mutants in Ca(2+) sensors that impair guard cell or plant ion channel signaling responses have not been identified, and whether Ca(2+)-independent ABA signaling mechanisms suffice for a full response remains unclear. Calcium-dependent protein kinases (CDPKs) have been proposed to contribute to central signal transduction responses in plants. However, no Arabidopsis CDPK gene disruption mutant phenotype has been reported to date, likely due to overlapping redundancies in CDPKs. Two Arabidopsis guard cell–expressed CDPK genes, CPK3 and CPK6, showed gene disruption phenotypes. ABA and Ca(2+) activation of slow-type anion channels and, interestingly, ABA activation of plasma membrane Ca(2+)-permeable channels were impaired in independent alleles of single and double cpk3cpk6 mutant guard cells. Furthermore, ABA- and Ca(2+)-induced stomatal closing were partially impaired in these cpk3cpk6 mutant alleles. However, rapid-type anion channel current activity was not affected, consistent with the partial stomatal closing response in double mutants via a proposed branched signaling network. Imposed Ca(2+) oscillation experiments revealed that Ca(2+)-reactive stomatal closure was reduced in CDPK double mutant plants. However, long-lasting Ca(2+)-programmed stomatal closure was not impaired, providing genetic evidence for a functional separation of these two modes of Ca(2+)-induced stomatal closing. Our findings show important functions of the CPK6 and CPK3 CDPKs in guard cell ion channel regulation and provide genetic evidence for calcium sensors that transduce stomatal ABA signaling

Updated Determination of D⁰–D¯⁰Mixing and CP Violation Parameters with D⁰→K⁺π⁻ Decays

We report measurements of charm-mixing parameters based on the decay-time-dependent ratio of D⁰→K⁺π⁻ to D⁰→K⁻π⁺ rates. The analysis uses a data sample of proton-proton collisions corresponding to an integrated luminosity of 5.0  fb⁻¹ recorded by the LHCb experiment from 2011 through 2016. Assuming charge-parity (CP) symmetry, the mixing parameters are determined to be x′²=(3.9±2.7)×10⁻⁵, y′=(5.28±0.52)×10⁻³, and R[subscript D]=(3.454±0.031)×10⁻³. Without this assumption, the measurement is performed separately for D⁰ and D[over ¯]⁰ mesons, yielding a direct CP-violating asymmetry A[subscript D]=(-0.1±9.1)×10⁻³, and magnitude of the ratio of mixing parameters 1.00<|q/p|<1.35 at the 68.3% confidence level. All results include statistical and systematic uncertainties and improve significantly upon previous single-measurement determinations. No evidence for CP violation in charm mixing is observed

Observation of D⁰ Meson Decays to Π⁺π⁻μ⁺μ⁻ and K⁺K⁻μ⁺μ⁻ Final States

The first observation of the D⁰→π⁺π⁻μ⁺μ⁻ and D⁰→K⁺K⁻μ⁺μ⁻ decays is reported using a sample of proton-proton collisions collected by LHCb at a center-of-mass energy of 8 TeV, and corresponding to 2  fb⁻¹ of integrated luminosity. The corresponding branching fractions are measured using as normalization the decay D⁰→K⁻π⁺[μ⁺μ⁻][subscript ρ⁰/ω], where the two muons are consistent with coming from the decay of a ρ⁰ or ω meson. The results are B(D⁰→π⁺π⁻μ⁺μ⁻)=(9.64±0.48±0.51±0.97)×10⁻⁷ and B(D⁰→K⁺K⁻μ⁺μ⁻)=(1.54±0.27±0.09±0.16)×10⁻⁷, where the uncertainties are statistical, systematic, and due to the limited knowledge of the normalization branching fraction. The dependence of the branching fraction on the dimuon mass is also investigated

Updated determination of D 0 - D 0 mixing and C P violation parameters with D 0 → K + π -

We report measurements of charm-mixing parameters based on the decay-time-dependent ratio of D0→K+π- to D0→K-π+ rates. The analysis uses a data sample of proton-proton collisions corresponding to an integrated luminosity of 5.0 fb-1 recorded by the LHCb experiment from 2011 through 2016. Assuming charge-parity (CP) symmetry, the mixing parameters are determined to be x′2=(3.9±2.7)×10-5, y′=(5.28±0.52)×10-3, and RD=(3.454±0.031)×10-3. Without this assumption, the measurement is performed separately for D0 and D0 mesons, yielding a direct CP-violating asymmetry AD=(-0.1±9.1)×10-3, and magnitude of the ratio of mixing parameters 1.00<|q/p|<1.35 at the 68.3% confidence level. All results include statistical and systematic uncertainties and improve significantly upon previous single-measurement determinations. No evidence for CP violation in charm mixing is observed

Search for CPCP violation through an amplitude analysis of D0→K+K−π+π−D^0 \to K^+ K^- \pi^+ \pi^- decays

International audienceA search for CP violation in the Cabibbo-suppressed D$^{0}$ → K$^{+}$K$^{−}$π$^{+}$π$^{−}$ decay mode is performed using an amplitude analysis. The measurement uses a sample of pp collisions recorded by the LHCb experiment during 2011 and 2012, corresponding to an integrated luminosity of 3.0 fb$^{−1}$. The D$^{0}$ mesons are reconstructed from semileptonic b-hadron decays into D$^{0}$μ$^{−}$X final states. The selected sample contains more than 160 000 signal decays, allowing the most precise amplitude modelling of this D$^{0}$ decay to date. The obtained amplitude model is used to perform the search for CP violation. The result is compatible with CP symmetry, with a sensitivity ranging from 1% to 15% depending on the amplitude considered

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion