Recombinant pediocin in Lactococcus lactis:increased production by propeptide fusion and improved potency by co-production with PedC

We describe the impact of two propeptides and PedC on the production yield and the potency of recombinant pediocins produced in Lactococcus lactis. On the one hand, the sequences encoding the propeptides SD or LEISSTCDA were inserted between the sequence encoding the signal peptide of Usp45 and the structural gene of the mature pediocin PA-1. On the other hand, the putative thiol-disulfide oxidoreductase PedC was coexpressed with pediocin. The concentration of recombinant pediocins produced in supernatants was determined by enzyme-linked immunosorbent assay. The potency of recombinant pediocins was investigated by measuring the minimal inhibitory concentration by agar well diffusion assay. The results show that propeptides SD or LEISSTCDA lead to an improved secretion of recombinant pediocins with apparently no effect on the antibacterial potency and that PedC increases the potency of recombinant pediocin. To our knowledge, this study reveals for the first time that pediocin tolerates fusions at the N-terminal end. Furthermore, it reveals that only expressing the pediocin structural gene in a heterologous host is not sufficient to get an optimal potency and requires the accessory protein PedC. In addition, it can be speculated that PedC catalyses the correct formation of disulfide bonds in pediocin.</p

Detection of opsonizing antibodies directed against a recently circulating Bordetella pertussis strain in paired plasma samples from symptomatic and recovered pertussis patients.

Correlates of protection (CoPs) against the highly contagious respiratory disease whooping cough, caused by Bordetella pertussis, remain elusive. Characterizing the antibody response to this pathogen is essential towards identifying potential CoPs. Here, we evaluate levels, avidity and functionality of B. pertussis-specific-antibodies from paired plasma samples derived from symptomatic and recovered pertussis patients, as well as controls. Natural infection is expected to induce protective immunity. IgG levels and avidity to nine B. pertussis antigens were determined using a novel multiplex panel. Furthermore, opsonophagocytosis of a B. pertussis clinical isolate by neutrophils was measured. Findings indicate that following infection, B. pertussis-specific antibody levels of (ex-) pertussis patients waned, while the avidity of antibodies directed against the majority of studied antigens increased. Opsonophagocytosis indices decreased upon recovery, but remained higher than controls. Random forest analysis of all the data revealed that 28% of the opsonophagocytosis index variances could be explained by filamentous hemagglutinin- followed by pertussis toxin-specific antibodies. We propose to further explore which other B. pertussis-specific antibodies can better predict opsonophagocytosis. Moreover, other B. pertussis-specific antibody functions as well as the possible integration of these functions in combination with other immune cell properties should be evaluated towards the identification of CoPs against pertussis

Melting over the northeast Antarctic Peninsula (1999-2009): evaluation of a high-resolution regional climate model

Surface melting over the Antarctic Peninsula (AP) may impact the stability of ice shelves and thus the rate at which grounded ice is discharged into the ocean. Energy and mass balance models are needed to understand how climatic change and atmospheric circulation variability drive current and future melting. In this study, we evaluate the regional climate model MAR over the AP at a 10km spatial resolution between 1999 and 2009, a period when active microwave data from the QuikSCAT mission is available. This model has been validated extensively over Greenland, has is applied here to the AP at a high resolution and for a relatively long time period (full outputs are available to 2014). We find that melting in the northeastern AP, the focus area of this study, can be initiated both by sporadic westerly föhn flow over the AP mountains and by northerly winds advecting warm air from lower latitudes. A comparison of MAR with satellite and automatic weather station (AWS) data reveals that satellite estimates show greater melt frequency, a larger melt extent, and a quicker expansion to peak melt extent than MAR in the centre and east of the Larsen C ice shelf. These differences are reduced in the north and west of the ice shelf, where the comparison with satellite data suggests that MAR is accurately capturing melt produced by warm westerly winds. MAR shows an overall warm bias and a cool bias at temperatures above 0°C as well as fewer warm, strong westerly winds than reported by AWS stations located on the eastern edge of the Larsen C ice shelf, suggesting that the underestimation of melt in this region may be the product of limited eastward flow. At higher resolutions (5km), MAR shows a further increase in wind biases and a decrease in meltwater production. We conclude that non-hydrostatic models at spatial resolutions better than 5km are needed to better-resolve the effects of föhn winds on the eastern edges of the Larsen C ice shelf

Melting over the northeast Antarctic Peninsula (1999-2009): evaluation of a high-resolution regional climate model

Surface melting over the Antarctic Peninsula (AP) may impact the stability of ice shelves and thus the rate at which grounded ice is discharged into the ocean. Energy and mass balance models are needed to understand how climatic change and atmospheric circulation variability drive current and future melting. In this study, we evaluate the regional climate model MAR over the AP at a 10km spatial resolution between 1999 and 2009, a period when active microwave data from the QuikSCAT mission is available. This model has been validated extensively over Greenland, has is applied here to the AP at a high resolution and for a relatively long time period (full outputs are available to 2014). We find that melting in the northeastern AP, the focus area of this study, can be initiated both by sporadic westerly föhn flow over the AP mountains and by northerly winds advecting warm air from lower latitudes. A comparison of MAR with satellite and automatic weather station (AWS) data reveals that satellite estimates show greater melt frequency, a larger melt extent, and a quicker expansion to peak melt extent than MAR in the centre and east of the Larsen C ice shelf. These differences are reduced in the north and west of the ice shelf, where the comparison with satellite data suggests that MAR is accurately capturing melt produced by warm westerly winds. MAR shows an overall warm bias and a cool bias at temperatures above 0°C as well as fewer warm, strong westerly winds than reported by AWS stations located on the eastern edge of the Larsen C ice shelf, suggesting that the underestimation of melt in this region may be the product of limited eastward flow. At higher resolutions (5km), MAR shows a further increase in wind biases and a decrease in meltwater production. We conclude that non-hydrostatic models at spatial resolutions better than 5km are needed to better-resolve the effects of föhn winds on the eastern edges of the Larsen C ice shelf

New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians

Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6 months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK), emergence of drug resistance, presence of comorbidities, and adverse drug reactions complicate TB therapy and drive the need for new drugs and/or regimens. Hence, new compounds are being developed, available drugs are repurposed, and the dosing of existing drugs is optimized, resulting in the largest drug development portfolio in TB history. This review highlights a selection of clinically available drug candidates that could be part of future TB regimens, including bedaquiline, delamanid, pretomanid, linezolid, clofazimine, optimized (high dose) rifampicin, rifapentine, and para-aminosalicylic acid. The review covers drug development history, preclinical data, PK, and current clinical development

High prevalence of advanced colorectal neoplasia and serrated polyposis syndrome in Hodgkin lymphoma survivors

Background: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors. Methods: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis. Results: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P <.001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P <.001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P =.08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P <.001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P <.001). Conclusions: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered

High prevalence of advanced colorectal neoplasia and serrated polyposis syndrome in Hodgkin lymphoma survivors

Background: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors. Methods: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis. Results: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P <.001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P <.001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P =.08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P <.001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P <.001). Conclusions: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered