Serum cytokine biosignatures for identification of tuberculosis among HIV-positive inpatients.

BACKGROUND: Serum cytokines correlate with tuberculosis (TB) progression and are predictors of TB recurrence in people living with HIV. We investigated whether serum cytokine biosignatures could diagnose TB among HIV-positive inpatients. METHODS: We recruited HIV-positive inpatients with symptoms of TB and measured serum levels of inflammation biomarkers including IL-2, IL-4, IL-6, IL-10, tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). We then built and tested our TB prediction model. RESULTS: 236 HIV-positive inpatients were enrolled in the first cohort and all the inflammation biomarkers were significantly higher in participants with microbiologically confirmed TB than those without TB. A binary support vector machine (SVM) model was built, incorporating the data of four biomarkers (IL-6, IL-10, TNF-α and IFN-γ). Efficacy of the SVM model was assessed in training (n=189) and validation (n=47) sets with area under the curve (AUC) of 0.92 (95% CI 0.88 to 0.96) and 0.85 (95% CI 0.72 to 0.97), respectively. In an independent test set (n=110), the SVM model yielded an AUC of 0.85 (95% CI 0.76 to 0.94) with 78% (95% CI 68% to 87%) specificity and 85% (95% CI 66% to 96%) sensitivity. Moreover, the SVM model outperformed interferon-gamma release assay (IGRA) among advanced HIV-positive inpatients irrespective of CD4+ T-cell counts, which may be an alternative approach for identifying Mycobacterium tuberculosis infection among HIV-positive inpatients with negative IGRA. CONCLUSIONS: The four-cytokine biosignature model successfully identified TB among HIV-positive inpatients. This diagnostic model may be an alternative approach to diagnose TB in advanced HIV-positive inpatients with low CD4+ T-cell counts.

C-terminal modification and functionalization of proteins via a self-cleavage tag triggered by a small molecule.

The precise modification or functionalization of the protein C-terminus is essential but full of challenges. Herein, a chemical approach to modify the C-terminus is developed by fusing a cysteine protease domain on the C-terminus of the protein of interest, which could achieve the non-enzymatic C-terminal functionalization by InsP6-triggered cysteine protease domain self-cleavage. This method demonstrates a highly efficient way to achieve protein C-terminal functionalization and is compatible with a wide range of amine-containing molecules and proteins. Additionally, a reversible C-terminal de-functionalization is found by incubating the C-terminal modified proteins with cysteine protease domain and InsP6, providing a tool for protein functionalization and de-functionalization. Last, various applications of protein C-terminal functionalization are provided in this work, as demonstrated by the site-specific assembly of nanobody drug conjugates, the construction of a bifunctional antibody, the C-terminal fluorescent labeling, and the C-terminal transpeptidation and glycosylation.

The effects of the renin inhibitor aliskiren on neuronal toxic damage.

The neurotoxicity of amyloid-ß (Aß) and its deposition in neurons plays a critical role in the occurrence and development of Alzheimer's disease (AD). Several preclinical experiments have found that the renin inhibitor aliskiren has a wide range of physiological effects, including hindering the progression of atherosclerosis and anti-inflammatory. This study is aimed to explore the effect of aliskiren on neuronal toxic damage and the underlying mechanism. This study established an in vitro nerve injury model through Aß 1-42 induction; the effects of aliskiren on the viability, inflammatory damage and apoptosis of SH-SY5Y cells were examined. For the sake of explore the underlying mechanism; SwissTargetPrediction website and molecular docking were utilized to predict the target of aliskiren. Then the impacts of the target protein overexpression were determined to verify its mediation. The results of the current study demonstrate that aliskiren has no effect on the viability of SH-SY5Y cells while Aß1-42accumulation could significantly downregulate cell viability. In addition, aliskiren could alleviate neuronal inflammatory damage and apoptosis arise from Aß 1-42accumulation. Following confirming the high expression level of the predicted target PDE4B in damaged cells, it was found that PDE4B overexpression can reverse the influence of aliskiren on cell viability, inflammatory damage and apoptosis. In conclusion, aliskiren upregulates cell viability, reduces inflammatory damage and apoptosis induced by Aß accumulation in AD via inhibiting PDE4B. These findings have expanded the scope of future application of aliskiren and provided a theoretical basis.