Dark Radiation from Particle Decays during Big Bang Nucleosynthesis

Cosmic microwave background (CMB) observations suggest the possibility of an extra dark radiation component, while the current evidence from big bang nucleosynthesis (BBN) is more ambiguous. Dark radiation from a decaying particle can affect these two processes differently. Early decays add an additional radiation component to both the CMB and BBN, while late decays can alter the radiation content seen in the CMB while having a negligible effect on BBN. Here we quantify this difference and explore the intermediate regime by examining particles decaying during BBN, i.e., particle lifetimes \tau_X satisfying 0.1 sec < \tau_X < 1000 sec. We calculate the change in the effective number of neutrino species, N_{eff}, as measured by the CMB, \Delta N_{CMB}, and the change in the effective number of neutrino species as measured by BBN, \Delta N_{BBN}, as a function of the decaying particle initial energy density and lifetime, where \Delta N_{BBN} is defined in terms of the number of additional two-component neutrinos needed to produce the same change in the primordial helium-4 abundance as our decaying particle. As expected, for short lifetimes (\tau_X < 0.1 sec), the particles decay before the onset of BBN, and \Delta N_{CMB} = \Delta N_{BBN}, while for long lifetimes (\tau_X > 1000 sec), \Delta N_{BBN} is dominated by the energy density of the nonrelativistic particles before they decay, so that \Delta N_{BBN} remains nonzero and becomes independent of the particle lifetime. By varying both the particle energy density and lifetime, one can obtain any desired combination of \Delta N_{BBN} and \Delta N_{CMB}, subject to the constraint that \Delta N_{CMB} >= \Delta N_{BBN}. We present limits on the decaying particle parameters derived from observational constraints on \Delta N_{CMB} and \Delta N_{BBN}.Comment: 6 pages, 3 figures, added figure and discussion of observational constraints, to appear in Phys. Rev.

Light Higgsino from Axion Dark Radiation

The recent observations imply that there is an extra relativistic degree of freedom coined dark radiation. We argue that the QCD axion is a plausible candidate for the dark radiation, not only because of its extremely small mass, but also because in the supersymmetric extension of the Peccei-Quinn mechanism the saxion tends to dominate the Universe and decays into axions with a sizable branching fraction. We show that the Higgsino mixing parameter mu is bounded from above when the axions produced at the saxion decays constitute the dark radiation: mu \lesssim 300 GeV for a saxion lighter than 2m_W, and mu less than the saxion mass otherwise. Interestingly, the Higgsino can be light enough to be within the reach of LHC and/or ILC even when the other superparticles are heavy with mass about 1 TeV or higher. We also estimate the abundance of axino produced by the decays of Higgsino and saxion.Comment: 18 pages, 1 figure; published in JHE

Structural insights into Clostridium perfringens delta toxin pore formation

Clostridium perfringens Delta toxin is one of the three hemolysin-like proteins produced by C. perfringens type C and possibly type B strains. One of the others, NetB, has been shown to be the major cause of Avian Nectrotic Enteritis, which following the reduction in use of antibiotics as growth promoters, has become an emerging disease of industrial poultry. Delta toxin itself is cytotoxic to the wide range of human and animal macrophages and platelets that present GM2 ganglioside on their membranes. It has sequence similarity with Staphylococcus aureus β-pore forming toxins and is expected to heptamerize and form pores in the lipid bilayer of host cell membranes. Nevertheless, its exact mode of action remains undetermined. Here we report the 2.4 Å crystal structure of monomeric Delta toxin. The superposition of this structure with the structure of the phospholipid-bound F component of S. aureus leucocidin (LukF) revealed that the glycerol molecules bound to Delta toxin and the phospholipids in LukF are accommodated in the same hydrophobic clefts, corresponding to where the toxin is expected to latch onto the membrane, though the binding sites show significant differences. From structure-based sequence alignment with the known structure of staphylococcal α-hemolysin, a model of the Delta toxin pore form has been built. Using electron microscopy, we have validated our model and characterized the Delta toxin pore on liposomes. These results highlight both similarities and differences in the mechanism of Delta toxin (and by extension NetB) cytotoxicity from that of the staphylococcal pore-forming toxins

Primary mediastinal large B-cell lymphoma (PMLBCL): long-term results from a retrospective multicentre Italian experience in 138 patients treated with CHOP or MACOP-B/VACOP-B

The optimal treatment of primary mediastinal large B-cell lymphoma (PMLBCL) is still undefined. In the absence of randomised studies, we retrospectively analysed: (a) the effectiveness of two chemotherapy regimens (CHOP vs MACOP-B/VACOP-B) in complete remission (CR) achievement and event-free survival (EFS) and (b) the role of mediastinal involved-field radiotherapy (IF-RT) as consolidation. From 1982 to 1999, 138 consecutive patients affected by PMLBCL were treated in 13 Italian institutions with CHOP (43) or MACOP-B/VACOP-B (95). The two groups of patients were similar as regard to age, gender, presence of bulky mediastinal mass, pleural effusion, stage and international prognostic indexes category of risk. Overall, 75.5% of patients in CR received IF-RT as consolidation. Complete remission was 51.1% in the CHOP group and 80% in MACOP-B/VACOP-B (P<0.001). Relapse occurred in 22.7% of CHOP- and in 9.2% of MACOP-B/VACOP-B-treated patients (n.s.). Event-free patients were 39.5% in CHOP and 75.7% in the MACOP-B/VACOP-B group (P<0.001). The addition of IF-RT as consolidation improved the outcome, irrespectively of the type of chemotherapy (P=0.04). At a multivariate analysis, achievement of CR (P<0.0001) and type of CT (MACOP-B/VACOP-B) retained the significance for OS (P=0.008) and EFS (P=0.03). In our experience, MACOP-B/VACOP-B appears to positively influence OS and EFS in patients affected by PMLBCL, as compared to CHOP. Consolidation IF-RT on mediastinum further improves the outcome of CR patients

Substrate Binding Mode and Its Implication on Drug Design for Botulinum Neurotoxin A

The seven antigenically distinct serotypes of Clostridium botulinum neurotoxins, the causative agents of botulism, block the neurotransmitter release by specifically cleaving one of the three SNARE proteins and induce flaccid paralysis. The Centers for Disease Control and Prevention (CDC) has declared them as Category A biowarfare agents. The most potent among them, botulinum neurotoxin type A (BoNT/A), cleaves its substrate synaptosome-associated protein of 25 kDa (SNAP-25). An efficient drug for botulism can be developed only with the knowledge of interactions between the substrate and enzyme at the active site. Here, we report the crystal structures of the catalytic domain of BoNT/A with its uncleavable SNAP-25 peptide 197QRATKM202 and its variant 197RRATKM202 to 1.5 Å and 1.6 Å, respectively. This is the first time the structure of an uncleavable substrate bound to an active botulinum neurotoxin is reported and it has helped in unequivocally defining S1 to S5′ sites. These substrate peptides make interactions with the enzyme predominantly by the residues from 160, 200, 250 and 370 loops. Most notably, the amino nitrogen and carbonyl oxygen of P1 residue (Gln197) chelate the zinc ion and replace the nucleophilic water. The P1′-Arg198, occupies the S1′ site formed by Arg363, Thr220, Asp370, Thr215, Ile161, Phe163 and Phe194. The S2′ subsite is formed by Arg363, Asn368 and Asp370, while S3′ subsite is formed by Tyr251, Leu256, Val258, Tyr366, Phe369 and Asn388. P4′-Lys201 makes hydrogen bond with Gln162. P5′-Met202 binds in the hydrophobic pocket formed by the residues from the 250 and 200 loop. Knowledge of interactions between the enzyme and substrate peptide from these complex structures should form the basis for design of potent inhibitors for this neurotoxin

Staphylococcus aureus Induces Eosinophil Cell Death Mediated by α-hemolysin

Staphylococcus aureus, a major human pathogen, exacerbates allergic disorders, including atopic dermatitis, nasal polyps and asthma, which are characterized by tissue eosinophilia. Eosinophils, via their destructive granule contents, can cause significant tissue damage, resulting in inflammation and further recruitment of inflammatory cells. We hypothesised that the relationship between S. aureus and eosinophils may contribute to disease pathology. We found that supernatants from S. aureus (SH1000 strain) cultures cause rapid and profound eosinophil necrosis, resulting in dramatic cell loss within 2 hours. This is in marked contrast to neutrophil granulocytes where no significant cell death was observed (at equivalent dilutions). Supernatants prepared from a strain deficient in the accessory gene regulator (agr) that produces reduced levels of many important virulence factors, including the abundantly produced α-hemolysin (Hla), failed to induce eosinophil death. The role of Hla in mediating eosinophil death was investigated using both an Hla deficient SH1000-modified strain, which did not induce eosinophil death, and purified Hla, which induced concentration-dependent eosinophil death via both apoptosis and necrosis. We conclude that S. aureus Hla induces aberrant eosinophil cell death in vitro and that this may increase tissue injury in allergic disease