Diversity of Raft-Like Domains in Late Endosomes

BACKGROUND: Late endosomes, the last sorting station in the endocytic pathway before lysosomes, are pleiomorphic organelles composed of tubular elements as well as vesicular regions with a characteristic multivesicular appearance, which play a crucial role in intracellular trafficking. Here, we have investigated whether, in addition to these morphologically distinguishable regions, late endosomal membranes are additionally sub-compartmentalized into membrane microdomains. METHODOLOGY/PRINCIPAL FINDINGS: Using sub-organellar fractionation techniques, both with and without detergents, combined with electron microscopy, we found that both the limiting membrane of the organel and the intraluminal vesicles contain raft-type membrane domains. Interestingly, these differentially localized domains vary in protein composition and physico-chemical properties. CONCLUSIONS/SIGNIFICANCE: In addition to the multivesicular organization, we find that late endosomes contain cholesterol rich microdomains both on their limiting membrane and their intraluminal vesicles that differ in composition and properties. Implications of these findings for late endosomal functions are discussed

Estimating health-adjusted life expectancy conditional on risk factors: results for smoking and obesity

BACKGROUND: Smoking and obesity are risk factors causing a large burden of disease. To help formulate and prioritize among smoking and obesity prevention activities, estimations of health-adjusted life expectancy (HALE) for cohorts that differ solely in their lifestyle (e.g. smoking vs. non smoking) can provide valuable information. Furthermore, in combination with estimates of life expectancy (LE), it can be tested whether prevention of obesity and smoking results in compression of morbidity. METHODS: Using a dynamic population model that calculates the incidence of chronic disease conditional on epidemiological risk factors, we estimated LE and HALE at age 20 for a cohort of smokers with a normal weight (BMI < 25), a cohort of non-smoking obese people (BMI>30) and a cohort of 'healthy living' people (i.e. non smoking with a BMI < 25). Health state valuations for the different cohorts were calculated using the estimated disease prevalence rates in combination with data from the Dutch Burden of Disease study. Health state valuations are multiplied with life years to estimate HALE. Absolute compression of morbidity is defined as a reduction in unhealthy life expectancy (LE-HALE) and relative compression as a reduction in the proportion of life lived in good health (LE-HALE)/LE. RESULTS: Estimates of HALE are highest for a 'healthy living' cohort (54.8 years for men and 55.4 years for women at age 20). Differences in HALE compared to 'healthy living' men at age 20 are 7.8 and 4.6 for respectively smoking and obese men. Differences in HALE compared to 'healthy living' women at age 20 are 6.0 and 4.5 for respectively smoking and obese women. Unhealthy life expectancy is about equal for all cohorts, meaning that successful prevention would not result in absolute compression of morbidity. Sensitivity analyses demonstrate that although estimates of LE and HALE are sensitive to changes in disease epidemiology, differences in LE and HALE between the different cohorts are fairly robust. In most cases, elimination of smoking or obesity does not result in absolute compression of morbidity but slightly increases the part of life lived in good health. CONCLUSION: Differences in HALE between smoking, obese and 'healthy living' cohorts are substantial and similar to differences in LE. However, our results do not indicate that substantial compression of morbidity is to be expected as a result of successful smoking or obesity prevention

Old World Arenaviruses Enter the Host Cell via the Multivesicular Body and Depend on the Endosomal Sorting Complex Required for Transport

The highly pathogenic Old World arenavirus Lassa virus (LASV) and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) use α-dystroglycan as a cellular receptor and enter the host cell by an unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Upon internalization, the viruses are delivered to acidified endosomes in a Rab5-independent manner bypassing classical routes of incoming vesicular trafficking. Here we sought to identify cellular factors involved in the unusual and largely unknown entry pathway of LASV and LCMV. Cell entry of LASV and LCMV required microtubular transport to late endosomes, consistent with the low fusion pH of the viral envelope glycoproteins. Productive infection with recombinant LCMV expressing LASV envelope glycoprotein (rLCMV-LASVGP) and LCMV depended on phosphatidyl inositol 3-kinase (PI3K) as well as lysobisphosphatidic acid (LBPA), an unusual phospholipid that is involved in the formation of intraluminal vesicles (ILV) of the multivesicular body (MVB) of the late endosome. We provide evidence for a role of the endosomal sorting complex required for transport (ESCRT) in LASV and LCMV cell entry, in particular the ESCRT components Hrs, Tsg101, Vps22, and Vps24, as well as the ESCRT-associated ATPase Vps4 involved in fission of ILV. Productive infection with rLCMV-LASVGP and LCMV also critically depended on the ESCRT-associated protein Alix, which is implicated in membrane dynamics of the MVB/late endosomes. Our study identifies crucial cellular factors implicated in Old World arenavirus cell entry and indicates that LASV and LCMV invade the host cell passing via the MVB/late endosome. Our data further suggest that the virus-receptor complexes undergo sorting into ILV of the MVB mediated by the ESCRT, possibly using a pathway that may be linked to the cellular trafficking and degradation of the cellular receptor

Search for Invisible Decays of a Dark Photon Produced in e(+)e(-) Collisions at BABAR

We search for single-photon events in 53 fb^-1 of e+e- collision data collected with the BaBar detector at the PEP-II B-factory. We look for events with a single high-energy photon and a large missing momentum and energy, consistent with production of a spin-1 particle A' through the process e+e->gamma A', A'->invisible. Such particles, referred to as "dark photons", are motivated by theories applying a U(1) gauge symmetry to dark matter. We find no evidence for such processes and set 90% confidence level upper limits on the coupling strength of A' to e+e- in the mass range m_A'<=8 GeV. In particular, our limits exclude the values of the A' coupling suggested by the dark-photon interpretation of the muon (g-2) anomaly, as well as a broad range of parameters for the dark-sector models.Comment: 9 pages, 13 figures; v2 is the version published in Physical Review Letter

Tests of CPT symmetry in B0- B 0 mixing and in B0 →c c K0 decays

Using the eight time dependences e-Γt(1+CicosΔmt+SisinΔmt) for the decays ϒ(4S)→B0B 0→fjfk, with the decay into a flavor-specific state fj=±X before or after the decay into a CP eigenstate fk=cc KS,L, as measured by the BABAR experiment, we determine the three CPT-sensitive parameters Re(z) and Im(z) in B0-B 0 mixing and |Ā/A| in B0→cc K0 decays. We find Im(z)=0.010±0.030±0.013, Re(z)=-0.065±0.028±0.014, and |Ā/A|=0.999±0.023±0.017, in agreement with CPT symmetry.</p

Searches for B(s)0 →J/ψpp‾ B_{(s)}^0\ \to {J \left/ {{\psi p}} \right.}\overline{p} and B + → J/ψ p p‾ \overline{p} π + decays

The results of searches for B0(s)→J/ψ pp¯ and B + → J/ψ p p¯ π+ decays are reported. The analysis is based on a data sample, corresponding to an integrated luminosity of 1.0 fb−1 of pp collisions, collected with the LHCb detector. An excess with 2.8 σ significance is seen for the decay B0s→J/ψ pp¯ and an upper limit on the branching fraction is set at the 90 % confidence level: B(B0s→J/ψ pp¯) &#60; 4.8 × 10−6, which is the first such limit. No significant signals are seen for B 0 → J/ψ p p¯ and B + → J/ψ p p¯ π + decays, for which the corresponding limits are set: B(B0→J/ψ pp¯) &#60; 5.2 × 10−7, which significantly improves the existing limit; and B(B+→J/ψ pp¯π+) &#60; 5.0 × 10−7, which is the first limit on this branching fraction

Study of the reactions e plus e- ? K+K-,r0,r0,r0, e+ e-?K0SK?,r?,r0,r0, and e plus e-? K0SK?,r?,r+,r- at center-of-mass energies from threshold to 4.5 GeV using initial-state radiation

We study the processes e+e-→K+K-π0π0π0γ, KS0K±π?π0π0γ, and KS0K±π?π+π-γ in which an energetic photon is radiated from the initial state. The data were collected with the BABAR detector at the SLAC National Accelerator Laboratory. About 1200, 2600, and 6000 events, respectively, are selected from a data sample corresponding to an integrated luminosity of 469 fb-1. The invariant mass of the hadronic final state defines the effective e+e- center-of-mass energy. The center-of-mass energies range from threshold to 4.5 GeV. From the mass spectra, the first ever measurements of the e+e-→K+K-π0π0π0, e+e-→KS0K±π?π0π0, and e+e-→KS0K±π?π+π- cross sections are performed. The contributions from the intermediate states that include η, φ, ρ, K∗(892), and other resonances are presented. We observe the J/ψ and ψ(2S) in most of these final states and measure the corresponding branching fractions, many of them for the first time

Search for a Stable Six-Quark State at BABAR

International audienceRecent investigations have suggested that the six-quark combination uuddss could be a deeply bound state (S) that has eluded detection so far, and a potential dark matter candidate. We report the first search for a stable, doubly strange six-quark state in ϒ→SΛ¯Λ¯ decays based on a sample of 90×106ϒ(2S) and 110×106ϒ(3S) decays collected by the BABAR experiment. No signal is observed, and 90% confidence level limits on the combined ϒ(2S,3S)→SΛ¯Λ¯ branching fraction in the range (1.2–1.4)×10-7 are derived for mS<2.05  GeV. These bounds set stringent limits on the existence of such exotic particles