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In this task, you're given a paragraph from the research paper and your task is to generate a suitable title for the research paper based on the given paper. Under 100 words is a good title length.
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Background: ISG15 is an Ubiquitin-like protein, highly induced by Type I Interferons. Upon the cooperative activity of specific Ubiquitinating enzymes, ISG15 can be conjugated to its substrates. Increasing evidence points to a role for protein ISGylation in anti-viral and anti-tumoral defense. Principal Findings: We identified ISG15 from Old World Monkeys (OWm) as a hyper-efficient protein modifier. Western blot analysis visualized more efficient conjugation of OWmISG15 relative to HuISG15 in human (Hu), monkey and mouse (Mo) cell-lines. Moreover, the substrates of OWmISG15 identified upon Tandem Affinity Purification followed by LC-MS/MS identification largely outnumbered these of HuISG15 itself. Several Ubiquitin-Conjugating enzymes were identified as novel ISGylated substrates. Introduction of a N89D mutation in HuISG15 improved its ISGylation capacity, and additional Q31K/ T33A/D133N mutations yielded a HuISG15 variant with an ISGylation efficiency comparable to OWmISG15. Homology modeling and structural superposition situate N89 in the interaction interface with the Activating enzyme. Analysis of the UbE1L residues in this interface revealed a striking homology between OWmUbE1L and HuUbE1, the Activating enzyme of Ubiquitin. In line with this observation, we found efficient activation of AgmISG15, but not HuISG15 or MoISG15, by HuUbE1, thus providing a likely explanation for OWm hyperISGylation. Conclusions: This study discloses the poor conjugation competence of HuISG15 compared to OWmISG15 and maps the critical determinants for efficient conjugation. HyperISGylation may greatly assist ISGylation studies and may enhance its function as positive regulator of Interferon-related immune responses or as anti-tumoral modulator.
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HyperISGylation of Old World Monkey ISG15 in Human Cells


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The lengthy duration of multidrug therapy needed to cure tuberculosis (TB) poses significant challenges for global control of the disease. Moreover, chronic inflammation associated with TB leads to pulmonary damage that can remain even after successful cure. Thus, there is a great need for the development of effective shorter drug regimens to improve clinical outcome and strengthen TB control. Host-directed therapy (HDT) is emerging as a novel adjunctive strategy to enhance the efficacy and shorten the duration of TB treatment. Previously, we showed that the administration of CC-3052, a phosphodiesterase-4 inhibitor (PDE4i), reduced the host inflammatory response during Mycobacterium tuberculosis (Mtb) infection and improved the antimicrobial efficacy of isoniazid (INH) in both the mouse and rabbit models. In the present study, we evaluated the pharmacokinetics and explored the mechanism underlying the efficacy of a more potent PDE4i, CC-11050, as adjunct to INH treatment in a mouse model of pulmonary Mtb infection. Genome-wide lung transcriptome analysis confirmed the dampening of inflammation and associated network genes that we previously reported with CC-3052. Consistent with the reduction in inflammation, a significant improvement in Mtb control and pathology was observed in the lungs of mice treated with CC-11050 plus INH, compared to INH alone. This important confirmatory study will be used to help design upcoming human clinical trials with CC-11050 as an HDT for TB treatment.
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Pharmacologic inhibition of host Phosphodiesterase-4 improves isoniazid-Mediated clearance of Mycobacterium tuberculosis


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Objective To describe how pandemic influenza A(H1N1)2009 [A (H1N1)pdm09] activity varied during the We calculated weekly proportions of A(H1N1)pdm09-positive specimens out of all A(H1N1)pdm09-positive specimens detected during the study period for each country. We compared parameters of pandemic activity (e.g., peak A[H1N1]pdm09 weekly proportion [peak activity], number of weeks between the 5th and 95th percentiles of A(H1N1)pdm09 cumulative weekly proportion [duration of activity]) between countries in temperate and tropical-subtropical regions. We quantified the proportion of A (H1N1)pdm09 out of all influenza A specimens by country and correlated it with countries' central latitudes. Results We analyzed data from 80 countries (47 temperate, 33 tropical-subtropical). The median proportion of cases identified during the peak week was higher in temperate (0Á12) than in tropical-subtropical (0Á09) regions (P < 0Á01). The median duration of activity was longer in tropical-subtropical (27 weeks) than in temperate countries (20 weeks) (P < 0Á01). In most temperate countries (98%), peak pandemic activity occurred during the fall-winter period. There was a positive correlation between country central latitude and proportion of A(H1N1)pdm09 out of all influenza A specimens (r: 0Á76; P < 0Á01). Conclusions The transmission of A(H1N1)pdm09 exhibited similarities with seasonal influenza transmission in that activity varied between temperate and tropical-subtropical countries and by time of year. Our findings suggest the potential utility of accounting for these factors during future pandemic planning. Keywords 2009 influenza A (H1N1), pandemic influenza, seasonality. Please cite this paper as: Storms et al. (2013) Worldwide transmission and seasonal variation of pandemic influenza A(H1N1)2009 virus activity during the
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Global Influenza Programme, World Health Organization