Novel peptides based on HIV-1 gp120 sequence with homology to chemokines inhibit HIV infection in cell culture

The sequential interaction of the envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) with CD4 and certain chemokine coreceptors initiates host cell entry of the virus. The appropriate chemokines have been shown to inhibit viral replication by blocking interaction of the gp120 envelope protein with the coreceptors. We considered the possibility that this interaction involves a motif of the gp120 that may be structurally homologous to the chemokines. In the amino acid sequences of most chemokines there is a Trp residue located at the beginning of the C-terminal α-helix, which is separated by six residues from the fourth Cys residue. The gp120 of all HIV-1 isolates have a similar motif, which includes the C-terminal part of a variable loop 3 (V3) and N-terminal part of a conserved region 3 (C3). Two synthetic peptides, derived from the relevant gp120 sequence inhibited HIV-1 replication in macrophages and T lymphocytes in sequence-dependent manner. The peptides also prevented binding of anti-CXCR4 antibodies to CXCR4, and inhibited the intracellular Ca(2+) influx in response to CXCL12/SDF-1α. Thus these peptides can be used to dissect gp120 interactions with chemokine receptors and could serve as leads for the design of new inhibitors of HIV-1.     

Identification of Rothia bacteria as gluten-degrading natural colonizers of the upper gastro-intestinal tract

Background

Gluten proteins, prominent constituents of barley, wheat and rye, cause celiac disease in genetically predisposed subjects. Gluten is notoriously difficult to digest by mammalian proteolytic enzymes and the protease-resistant domains contain multiple immunogenic epitopes. The aim of this study was to identify novel sources of gluten-digesting microbial enzymes from the upper gastro-intestinal tract with the potential to neutralize gluten epitopes.

Methodology/Principal Findings

Oral microorganisms with gluten-degrading capacity were obtained by a selective plating strategy using gluten agar. Microbial speciations were carried out by 16S rDNA gene sequencing. Enzyme activities were assessed using gliadin-derived enzymatic substrates, gliadins in solution, gliadin zymography, and 33-mer α-gliadin and 26-mer γ-gliadin immunogenic peptides. Fragments of the gliadin peptides were separated by RP-HPLC and structurally characterized by mass spectrometry. Strains with high activity towards gluten were typed as Rothia mucilaginosa and Rothia aeria. Gliadins (250 µg/ml) added to Rothia cell suspensions (OD₆₂₀ 1.2) were degraded by 50% after ∼30 min of incubation. Importantly, the 33-mer and 26-mer immunogenic peptides were also cleaved, primarily C-terminal to Xaa-Pro-Gln (XPQ) and Xaa-Pro-Tyr (XPY). The major gliadin-degrading enzymes produced by the Rothia strains were ∼70–75 kDa in size, and the enzyme expressed by Rothia aeria was active over a wide pH range (pH 3–10).

Conclusion/Significance

While the human digestive enzyme system lacks the capacity to cleave immunogenic gluten, such activities are naturally present in the oral microbial enzyme repertoire. The identified bacteria may be exploited for physiologic degradation of harmful gluten peptides.     

Divergen properties of two human lymphocytic cell lines isolated from a single specimen of peripheral blood

Summary Two lymphocytic cell lines were obtained from a single specimen of peripheral blood buffy coat from a patient with acute lymphoblastic leukemia who concurrently developed classical infectious mononucleosis. These two cell lines exhibit distinguishing differences in culture in parallel with reviously described differences in the cells when implanted into eonatal Syrian hamsters. These observations suggest that the cell lines were derived from two pre-existing different classes or “stelines” of cells—one of which resembles other cell lines derived from patients with acute lymphoblastic leukemia, whereas the other resembles cell lines derived from other, patients with infecttious mononucleosis. These studies were suported in part by research Grants C-6516 from the National Cancer Institute and FR-05526 from the Division of Research Facilities and Resources, National Institutes of Health.     

Degraded Time-Frequency Acuity to Time-Reversed Notes

Time-reversal symmetry breaking is a key feature of many classes of natural sounds, originating in the physics of sound production. While attention has been paid to the response of the auditory system to “natural stimuli,” very few psychophysical tests have been performed. We conduct psychophysical measurements of time-frequency acuity for stylized representations of “natural”-like notes (sharp attack, long decay) and the time-reversed versions of these notes (long attack, sharp decay). Our results demonstrate significantly greater precision, arising from enhanced temporal acuity, for such sounds over their time-reversed versions, without a corresponding decrease in frequency acuity. These data inveigh against models of auditory processing that include tradeoffs between temporal and frequency acuity, at least in the range of notes tested and suggest the existence of statistical priors for notes with a sharp-attack and a long-decay. We are additionally able to calculate a minimal theoretical bound on the sophistication of the nonlinearities in auditory processing. We find that among the best studied classes of nonlinear time-frequency representations, only matching pursuit, spectral derivatives, and reassigned spectrograms are able to satisfy this criterion.