Biochemical Engineering of Surface α2–8 Polysialic Acid for Immunotargeting Tumor Cells

To target tumor cells for immunotherapy, we evaluated the feasibility of altering the epitopes on the surface polysialic acid of tumor cells. A precursor (N-propionylmannosamine), when incubated with leukemic cells, RBL-2H3 and RMA, resulted in substitution of the N-acetyl groups of surface alpha2-8 polysialic acid with N-propionyl groups. Expression of the altered alpha2-8 N-propionylpolysialic acid on the surface of tumor cells induced their susceptibility to cell death mediated by monoclonal antibody 13D9 (mAb 13D9), which specifically recognizes alpha2-8 N-propionylated polysialic acid. The expression of alpha2-8 N-propionylated polysialic acid and the lysis of tumor cells by antibody-dependent cytotoxicity depended on the time and dose of incorporation of N-propionylated mannosamine. In vivo, mAb 13D9 effectively controlled metastasis of leukemic cells RMA when mice were administered the precursor N-propionylated mannosamine

Airway microbiome in adult survivors of extremely preterm birth: the EPICure study

Bronchopulmonary Dysplasia(BPD) is a major complication of preterm birth that leads to lifelong respiratory morbidity. The EPICure study has investigated the longitudinal health outcomes of infants born extremely preterm (<26 weeks-gestation). Our aim was to characterise the airway microbiome in young adults born extremely preterm (EP), with and without neonatal BPD, in comparison to matched term-born controls.Induced sputum was collected from 92 young adults age 19 years (51 EP and 41 controls). Typical respiratory pathogens were detected using quantitative-PCR. 16S-rRNA gene sequencing was completed on 74 samples (29 EP with BPD, 9 EP without BPD and 36 controls).The preterm group with BPD had the least diverse bacterial communities. The relative-abundance of Bacteriodetes, particularly Prevotella melaninogenica was significantly lower in the preterm group compared to controls. This decline was balanced by a nonsignificant increase in Firmicutes. Total Prevotella relative-abundance correlated with FEV1 z-score (ρ=0.272; p<0.05). Typical respiratory pathogens loads and prevalence were similar between groups.In conclusion, extremely preterm birth is associated with a significant dysbiosis in airway microbiome in young adulthood regardless of neonatal BPD status. This is characterised by a shift in the community composition away from Bacteriodetes as manifested in a significant drop in Prevotella relative-abundance

Limitations of the pour point measurement and the influence of the oil composition on its detection using principal component analysis

A method for maximum and minimum pour point determination in crude oil was applied, and the chemical composition of 80 samples, American Petroleum Institute (API) gravity, total acid number (TAN), density, kinematic viscosity, and sulfur, asphaltene, and wax contents were analyzed in association with chemometric methods. The results of the 80 analyzed samples showed maximum pour point temperatures from 9 to -36 degrees C and minimum pour point temperatures from 12 to -36 degrees C. Heavy oils with asphaltenic chemical composition showed more positive values of pour point (5-8 degrees C) and showed no significant difference between the maximum and minimum pour points considering the repeatability of the method (3 degrees C for maximum and 6 degrees C for minimum). However, the oils with chemical composition with higher wax content and higher API gravity showed lower pour point values from -24 to -6 degrees C (maximum) and from -30 to -18 degrees C (minimum), respectively. The principal component analysis (PCA) explained 92% of data variability, showing that the differences among the properties of the samples allowed for their separation by groups and some properties are closely correlated to the pour point2831686169

A qualitative risk assessment for visual-only post-mortem meat inspection of cattle, sheep, goats and farmed/wild deer

The UK Food Standards Agency is currently funding research to build the evidence base for the modernisation of meat inspection. This includes an assessment of the risks to public health and animal health/welfare of moving to a visual-only post-mortem meat inspection (PMMI), where routine mandatory palpation and incision procedures are omitted. In this paper we present the results of a risk assessment for a change from current to visual-only PMMI for cattle, sheep/goats and farmed/wild deer. A large list of hazard/species pairings were assessed and prioritised by a process of hazard identification. Twelve hazard/species pairings were selected for full consideration within the final risk assessment. The results of the public health risk assessment indicated that all hazard/species pairings were Negligible with the exception of Cysticercus bovis in cattle, which was judged to be of low-medium increased risk for systems not conforming to criteria as laid down by EC Regulation 1244/2007, compared to systems that do conform to Regulations for visual-only PMMI. Most hazard/species pairings were concluded to pose a potential increased risk to animal health/welfare, including Mycobacterium bovis (very low – low increase in risk, but with considerable uncertainty), Fasciola hepatica (negligible – very low) and Cysticercus bovis (very low – low). Due to low feedback rates to farmers, the real risk to animal health/welfare for F. hepatica and C. bovis, including animals in non-conforming systems under visual-only PMMI, is probably negligible. That then leaves M. bovis as the only confirmed non-negligible animal health and welfare risk

A Burgessian critique of nominalistic tendencies in contemporary mathematics and its historiography

We analyze the developments in mathematical rigor from the viewpoint of a Burgessian critique of nominalistic reconstructions. We apply such a critique to the reconstruction of infinitesimal analysis accomplished through the efforts of Cantor, Dedekind, and Weierstrass; to the reconstruction of Cauchy's foundational work associated with the work of Boyer and Grabiner; and to Bishop's constructivist reconstruction of classical analysis. We examine the effects of a nominalist disposition on historiography, teaching, and research.Comment: 57 pages; 3 figures. Corrected misprint

Baseline and acquired resistance to bedaquiline, linezolid and pretomanid, and impact on treatment outcomes in four tuberculosis clinical trials containing pretomanid.

Bedaquiline (B), pretomanid (Pa) and linezolid (L) are key components of new regimens for treating rifampicin-resistant tuberculosis (TB). However, there is limited information on the global prevalence of resistance to these drugs and the impact of resistance on treatment outcomes. Mycobacterium tuberculosis (MTB) phenotypic drug susceptibility and whole-genome sequence (WGS) data, as well as patient profiles from 4 pretomanid-containing trials-STAND, Nix-TB, ZeNix and SimpliciTB-were used to investigate the rates of baseline resistance (BR) and acquired resistance (AR) to BPaL drugs, as well as their genetic basis, risk factors and impact on treatment outcomes. Data from >1,000 TB patients enrolled from 2015 to 2020 in 12 countries was assessed. We identified 2 (0.3%) participants with linezolid BR. Pretomanid BR was also rare, with similar rates across TB drug resistance types (0-2.1%). In contrast, bedaquiline BR was more prevalent among participants with highly resistant TB or longer prior treatment histories than those with newly diagnosed disease (5.2-6.3% vs. 0-0.3%). Bedaquiline BR was a risk factor for bacteriological failure or relapse in Nix-TB/ZeNix; 3/12 (25%, 95% CI 5-57%) participants with vs. 6/185 (3.2%, 1.2-6.9%) without bedaquiline BR. Across trials, we observed no linezolid AR, and only 3 cases of bedaquiline AR, including 2 participants with poor adherence. Overall, pretomanid AR was also rare, except in ZeNix patients with bedaquiline BR. WGS analyses revealed novel mutations in canonical resistant genes and, in 7 MTB isolates, the genetic determinants could not be identified. The overall low rates of BR to linezolid and pretomanid, and to a lesser extent to bedaquiline, observed in the pretomanid trials are in support of the worldwide implementation of BPaL-based regimens. Similarly, the overall low AR rates observed suggest BPaL drugs are better protected in the regimens trialed here than in other regimens combining bedaquiline with more, but less effective drugs

Voices from the past: early institutional experience of children with disabilities - the case of Scotland

In Scotland, public interest in children with disabilities followed an uneven path. The proponents for such interest included workers in medicine, education and training, public administration, law and order, religion and moral rectitude, philanthropy and charity. Their foci of attention were similarly divers. Initial attention towards children with ‘disabilities’ was directed towards those with sensory impairments. This was followed by provision for children with mental disabilities. Until the introduction of compulsory education in 1872, philanthropists and charities were largely unaware of children with physical impairments. The Scottish experience was distinctive from the rest of the United Kingdom because of its own legal system, and was set against a background of heavy industrialization accompanied by poverty and bad housing. Legislation in such areas as poor law reform and education was not introduced simultaneously to that for England and Wales. The Church of Scotland maintained a strong influence in local government, through the network of clearly defined parishes, despite the secularization that was intent in such legislation as the Poor Law (Scotland) Act of 1843. The influence of Presbyterian clergymen and church elders committed to strongly held ideals of religious belief, respectability and self-help is often apparent in the institutions established for children with disabilities. The following research makes use of archival sources on institutions receiving, accommodating and caring for children with disabilities, supplemented by some contemporary narrative and oral testimony. While the archival sources show that the attention paid to children with disabilities did not develop simultaneously for categories of impairment broadly grouped as sensory, mental and physical, they also indicate that the responses to different forms of disablement followed diverse approaches and objectives

Demographic predictors of wellbeing in Carers of people with psychosis: secondary analysis of trial data

Background: Carers of people with psychosis are at a greater risk of physical and mental health problems compared to the general population. Yet, not all carers will experience a decline in health. This predicament has provided the rationale for research studies exploring what factors predict poor wellbeing in carers of people with psychosis. Our study builds on previous research by testing the predictive value of demographic variables on carer wellbeing within a single regression model. Methods: To achieve this aim, we conducted secondary analysis on two trial data sets that were merged and recoded for the purposes of this study. Results: Contrary to our hypotheses, only carer gender and age predicted carer wellbeing; with lower levels of carer wellbeing being associated with being female or younger (aged under 50). However, the final regression model explained only 11% of the total variance. Conclusions: Suggestions for future research are discussed in light of the limitations inherent in secondary analysis studies. Further research is needed where sample sizes are sufficient to explore the interactive and additive impact of other predictor variables

The Acute Environment, Rather than T Cell Subset Pre-Commitment, Regulates Expression of the Human T Cell Cytokine Amphiregulin

Cytokine expression patterns of T cells can be regulated by pre-commitment to stable effector phenotypes, further modification of moderately stable phenotypes, and quantitative changes in cytokine production in response to acute signals. We showed previously that the epidermal growth factor family member Amphiregulin is expressed by T cell receptor-activated mouse CD4 T cells, particularly Th2 cells, and helps eliminate helminth infection. Here we report a detailed analysis of the regulation of Amphiregulin expression by human T cell subsets. Signaling through the T cell receptor induced Amphiregulin expression by most or all T cell subsets in human peripheral blood, including naive and memory CD4 and CD8 T cells, Th1 and Th2 in vitro T cell lines, and subsets of memory CD4 T cells expressing several different chemokine receptors and cytokines. In these different T cell types, Amphiregulin synthesis was inhibited by an antagonist of protein kinase A, a downstream component of the cAMP signaling pathway, and enhanced by ligands that increased cAMP or directly activated protein kinase A. Prostaglandin E2 and adenosine, natural ligands that stimulate adenylyl cyclase activity, also enhanced Amphiregulin synthesis while reducing synthesis of most other cytokines. Thus, in contrast to mouse T cells, Amphiregulin synthesis by human T cells is regulated more by acute signals than pre-commitment of T cells to a particular cytokine pattern. This may be appropriate for a cytokine more involved in repair than attack functions during most inflammatory responses

Priming with recombinant auxotrophic BCG expressing HIV-1 Gag, RT and Gp120 and boosting with recombinant MVA induces a robust T cell response in mice

In previous studies we have shown that a pantothenate auxotroph of Myocbacterium bovis BCG (BCGΔ panCD ) expressing HIV-1 subtype C Gag induced Gag-specific immune responses in mice and Chacma baboons after prime-boost immunization in combination with matched rMVA and VLP vaccines respectively. In this study recombinant BCG (rBCG) expressing HIV-1 subtype C reverse transcriptase and a truncated envelope were constructed using both the wild type BCG Pasteur strain as a vector and the pantothenate auxotroph. Mice were primed with rBCG expressing Gag and RT and boosted with a recombinant MVA, expressing a polyprotein of Gag, RT, Tat and Nef (SAAVI MVA-C). Priming with rBCGΔ panCD expressing Gag or RT rather than the wild type rBCG expressing Gag or RT resulted in higher frequencies of total HIV-specific CD8 + T cells and increased numbers of T cells specific to the subdominant Gag and RT epitopes. Increasing the dose of rBCG from 10 5 cfu to 10 7 cfu also led to an increase in the frequency of responses to subdominant HIV epitopes. A mix of the individual rBCGΔ panCD vaccines expressing either Gag, RT or the truncated Env primed the immune system for a boost with SAAVI MVA-C and generated five-fold higher numbers of HIV-specific IFN-γ-spot forming cells than mice primed with rBCGΔ panCD containing an empty vector control. Priming with the individual rBCGΔ panCD vaccines or the mix and boosting with SAAVI MVA-C also resulted in the generation of HIV-specific CD4 + and CD8 + T cells producing IFN-γ and TNF-α and CD4 + cells producing IL-2. The rBCG vaccines tested in this study were able to prime the immune system for a boost with rMVA expressing matching antigens, inducing robust, HIV-specific T cell responses to both dominant and subdominant epitopes in the individual proteins when used as individual vaccines or in a mix