Admission Neutrophil-to-Lymphocyte Ratio as a Predictive Factor in the Outcome of Acute Spontaneous Intracerebral Hemorrhage.

Background and Objective: A growing body of evidence supports that inflammatory mechanisms are involved in secondary brain injury after intracerebral hemorrhage (ICH) which has implications on the morbidity and mortality of stroke patients. Neutrophil-to-lymphocyte ratio (NLR) is a comprehensive index marker of inflammation and immune status of a patient. The prognostic value of NLR in predicting in-hospital mortality and functional outcome of patients with spontaneous intracerebral hemorrhage will be assessed in this study. Methods: We retrospectively selected 151 hemorrhagic stroke patients, and demographic and clinical characteristics were collected and computed for NLR. Receiver operating characteristic analysis using Youden's index was utilized to determine the NLR cut-off value with the best sensitivity and specificity. The association of NLR with the in-hospital mortality and functional outcome was assessed using Logistic regression analysis. Pearson Product Model Correlation was employed to evaluate the correlation of NLR with ICH volume. Results: Admission NLR >7 showed a significant association (p=<0.001 OR 7.99) with in-hospital mortality with a sensitivity of 70.83% and specificity of 72.82%. Furthermore, computed NLR of more than 6.4 showed significant association (p=0.040 OR 2.92) with poor functional outcome. However, our study revealed that admission NLR showed a low level of correlation (r=0.2968, p=0.002) with the volume of ICH. CONCLUSION: This study demonstrated that ICH patients with an elevated NLR is associated with increased in-hospital mortality and poor functional outcome and that NLR can be used to predict clinical outcome among patients with spontaneous ICH.

FAM105A/OTULINL Is a Pseudodeubiquitinase of the OTU-Class that Localizes to the ER Membrane.

Pseudoenzymes have been identified across a diverse range of enzyme classes and fulfill important cellular functions. Examples of pseudoenzymes exist within ubiquitin conjugating and deubiquitinase (DUB) protein families. Here we characterize FAM105A/OTULINL, the only putative pseudodeubiquitinase of the ovarian tumor protease (OTU domain) family in humans. The crystal structure of FAM105A revealed that the OTU domain possesses structural deficiencies in both active site and substrate-binding infrastructure predicted to impair normal DUB function. We confirmed the absence of catalytic function against all ubiquitin linkages and an inability of FAM105A to bind ubiquitin compared with catalytically active FAM105B/OTULIN. FAM105A co-localized with KDEL markers and Lamin B1 at the endoplasmic reticulum (ER) and nuclear envelope, respectively. Accordingly, the FAM105A interactome exhibited significant enrichment in proteins localized to the ER/outer nuclear, Golgi and vesicular membranes. In light of undetectable deubiquitinase activity, we posit that FAM105A/OTULINL functions through its ability to mediate protein-protein interactions.

Nonnative interactions regulate folding and switching of myristoylated protein.

We present an integrated experimental and computational study of the molecular mechanisms by which myristoylation affects protein folding and function, which has been little characterized to date. Myristoylation, the covalent linkage of a hydrophobic C14 fatty acyl chain to the N-terminal glycine in a protein, is a common modification that plays a critical role in vital regulated cellular processes by undergoing reversible energetic and conformational switching. Coarse-grained folding simulations for the model pH-dependent actin- and membrane-binding protein hisactophilin reveal that nonnative hydrophobic interactions of the myristoyl with the protein as well as nonnative electrostatic interactions have a pronounced effect on folding rates and thermodynamic stability. Folding measurements for hydrophobic residue mutations of hisactophilin and atomistic simulations indicate that the nonnative interactions of the myristoyl group in the folding transition state are nonspecific and robust, and so smooth the energy landscape for folding. In contrast, myristoyl interactions in the native state are highly specific and tuned for sensitive control of switching functionality. Simulations and amide hydrogen exchange measurements provide evidence for increases as well as decreases in stability localized on one side of the myristoyl binding pocket in the protein, implicating strain and altered dynamics in switching. The effects of folding and function arising from myristoylation are profoundly different from the effects of other post-translational modifications.