39 research outputs found
Blood transcriptomic discrimination of bacterial and viral infections in the emergency department: a multi-cohort observational validation study
Background: There is an urgent need to develop biomarkers that stratify risk of bacterial infection in order to support antimicrobial stewardship in emergency hospital admissions. / Methods: We used computational machine learning to derive a rule-out blood transcriptomic signature of bacterial infection (SeptiCyteâ„¢ TRIAGE) from eight published case-control studies. We then validated this signature by itself in independent case-control data from more than 1500 samples in total, and in combination with our previously published signature for viral infections (SeptiCyteâ„¢ VIRUS) using pooled data from a further 1088 samples. Finally, we tested the performance of these signatures in a prospective observational cohort of emergency department (ED) patients with fever, and we used the combined SeptiCyteâ„¢ signature in a mixture modelling approach to estimate the prevalence of bacterial and viral infections in febrile ED patients without microbiological diagnoses. / Results:
The combination of SeptiCyte™ TRIAGE with our published signature for viral infections (SeptiCyte™ VIRUS) discriminated bacterial and viral infections in febrile ED patients, with a receiver operating characteristic area under the curve of 0.95 (95% confidence interval 0.90–1), compared to 0.79 (0.68–0.91) for WCC and 0.73 (0.61–0.86) for CRP. At pre-test probabilities 0.35 and 0.72, the combined SeptiCyte™ score achieved a negative predictive value for bacterial infection of 0.97 (0.90–0.99) and 0.86 (0.64–0.96), compared to 0.90 (0.80–0.94) and 0.66 (0.48–0.79) for WCC and 0.88 (0.69–0.95) and 0.60 (0.31–0.72) for CRP. In a mixture modelling approach, the combined SeptiCyte™ score estimated that 24% of febrile ED cases receiving antibacterials without a microbiological diagnosis were due to viral infections. Our analysis also suggested that a proportion of patients with bacterial infection recovered without antibacterials. / Conclusions: Blood transcriptional biomarkers offer exciting opportunities to support precision antibacterial prescribing in ED and improve diagnostic classification of patients without microbiologically confirmed infections
Prion-like p53 amyloids in cancer
The global transcription factor, p53, is a master regulator of gene expression in cells. Mutations in the TP53 gene promote unregulated cell growth through the inactivation of downstream effectors of the p53 pathway. In fact, mutant p53 is highly prone to misfolding and frequently resides inside the cell as large aggregates, causing loss of physiological function of the tumor-suppressor protein. Here, we review the plausible reasons for functional loss of p53, including amyloid formation leading to unhindered cancer progression. We discuss previous as well as recent findings regarding the amyloid formation of p53 in vitro and in vivo. We elaborate on prion-like properties of p53 amyloids and their possible involvement in cancer progression. Because the p53 pathway is historically most targeted for the development of anticancer therapeutics, we have also summarized some of the recent approaches and advances in reviving the antiproliferative activities of wild-type p53. In this Perspective, we provide insight into understanding p53 as a prion-like protein and propose cancer to be recognized as an amyloid or prion-like disease
Complexation of NAC-Derived Peptide Ligands with the C‑Terminus of α‑Synuclein Accelerates Its Aggregation
Aggregation
of α-synuclein (α-Syn) into neurotoxic
oligomers and amyloid fibrils is suggested to be the pathogenic mechanism
for Parkinson’s disease (PD). Recent studies have indicated
that oligomeric species of α-Syn are more cytotoxic than their
mature fibrillar counterparts, which are responsible for dopaminergic
neuronal cell death in PD. Therefore, the effective therapeutic strategies
for tackling aggregation-associated diseases would be either to prevent
aggregation or to modulate the aggregation process to minimize the
formation of toxic oligomers during aggregation. In this work, we
showed that arginine-substituted α-Syn ligands, based on the
most aggregation-prone sequence of α-Syn, accelerate the protein
aggregation in a concentration-dependent manner. To elucidate the
mechanism by which Arg-substituted peptides could modulate α-Syn
aggregation kinetics, we performed surface plasmon resonance (SPR)
spectroscopy, nuclear magnetic resonance (NMR) studies, and all-atom
molecular dynamics (MD) simulation. The SPR analysis showed a high
binding potency of these peptides with α-Syn but one that was
nonspecific in nature. The two-dimensional NMR studies suggest that
a large stretch within the C-terminus of α-Syn displays a chemical
shift perturbation upon interacting with Arg-substituted peptides,
indicating C-terminal residues of α-Syn might be responsible
for this class of peptide binding. This is further supported by MD
simulation studies in which the Arg-substituted peptide showed the
strongest interaction with the C-terminus of α-Syn. Overall,
our results suggest that the binding of Arg-substituted ligands to
the highly acidic C-terminus of α-Syn leads to reduced charge
density and flexibility, resulting in accelerated aggregation kinetics.
This may be a potentially useful strategy while designing peptides,
which act as α-Syn aggregation modulators