Chitinase and Fizz family members are a generalized feature of nematode infection with selective Upregulation of Ym1 and F10.1 by antigen-presenting cells

Ym1 and Fizz1 are secreted proteins that have been identified in a variety of Th2-mediated inflammatory settings. We originally found Ym1 and Fizz1 as highly expressed macrophage genes in a Brugia malayi infection model. Here, we show that their expression is a generalized feature of nematode infection and that they are induced at the site of infection with both the tissue nematode Litomosoides sigmodontis and the gastrointestinal nematode Nippostrongylus brasiliensis. At the sites of infection with N. brasiliensis, we also observed induction of other chitinase and Fizz family members (ChaFFs): acidic mammalian chitinase (AMCase) and Fizz2. The high expression of both Ym1 and AMCase in the lungs of infected mice suggests that abundant chitinase production is an important feature of Th2 immune responses in the lung. In addition to expression of ChaFFs in the tissues, Ym1 and Fizz1 expression was observed in the lymph nodes. Expression both in vitro and in vivo was restricted to antigen-presenting cells, with the highest expression in B cells and macrophages. ChaFFs may therefore be important effector or wound-repair molecules at the site of nematode infection, with potential regulatory roles for Ym1 and Fizz1 in the draining lymph nodes

Effect of variation in mesh size on trawl efficiency

Result of comparative fishing trials with a bulged belly design with three different mesh ranges in the body and wing to study the effect of mesh size difference on the performance of gear is discussed. While there is no significant difference in catch rate, predictably the 40 mm mesh size trawl fared wen when small sized fish like anchovies formed the major catch. The trawls with 60 and 80 mm mesh size gave better horizontal spread at a lower resistance showing savings in fuel

Initial antimicrobial management of sepsis.

Sepsis is a common consequence of infection, associated with a mortality rate > 25%. Although community-acquired sepsis is more common, hospital-acquired infection is more lethal. The most common site of infection is the lung, followed by abdominal infection, catheter-associated blood steam infection and urinary tract infection. Gram-negative sepsis is more common than gram-positive infection, but sepsis can also be due to fungal and viral pathogens. To reduce mortality, it is necessary to give immediate, empiric, broad-spectrum therapy to those with severe sepsis and/or shock, but this approach can drive antimicrobial overuse and resistance and should be accompanied by a commitment to de-escalation and antimicrobial stewardship. Biomarkers such a procalcitonin can provide decision support for antibiotic use, and may identify patients with a low likelihood of infection, and in some settings, can guide duration of antibiotic therapy. Sepsis can involve drug-resistant pathogens, and this often necessitates consideration of newer antimicrobial agents

Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides

Thiopeptides are a broad class of macrocyclic, heavily modified peptide natural products that are unified by the presence of a substituted, nitrogen-containing heterocycle core. Early work indicated that this core might be fashioned from two dehydroalanines by an enzyme-catalyzed aza-[4 + 2] cycloaddition to give a cyclic-hemiaminal intermediate. This common intermediate could then follow a reductive path toward a dehydropiperidine, as in the thiopeptide thiostrepton, or an aromatization path to yield the pyridine groups observed in many other thiopeptides. Although several of the enzymes proposed to perform this cycloaddition have been reconstituted, only pyridine products have been isolated and any hemiaminal intermediates have yet to be observed. Here, we identify the conditions and substrates that decouple the cycloaddition from subsequent steps and allow interception and characterization of this long hypothesized intermediate. Transition state modeling indicates that the key amide-iminol tautomerization is the major hurdle in an otherwise energetically favorable cycloaddition. An anionic model suggests that deprotonation and polarization of this amide bond by TbtD removes this barrier and provides a sufficient driving force for facile (stepwise) cycloaddition. This work provides evidence for a mechanistic link between disparate cyclases in thiopeptide biosynthesis

Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance

Colorectal cancer (CRC) is the third most prevalent cancer worldwide with a high mortality rate (20–30%), especially due to metastasis to adjacent organs. Clinical responses to chemotherapy, radiation, targeted and immunotherapies are limited to a subset of patients making metastatic CRC (mCRC) difficult to treat. To understand the therapeutic modulation of immune response in mCRC, we have used a genetically engineered mouse model (GEMM), “KPN”, which resembles the human ‘CMS4’-like subtype. We show here that transforming growth factor (TGF-β1), secreted by KPN organoids, increases cancer cell proliferation, and inhibits splenocyte activation in vitro. TGF-β1 also inhibits activation of naive but not pre-activated T cells, suggesting differential effects on specific immune cells. In vivo, the inhibition of TGF-β inflames the KPN tumors, causing infiltration of T cells, monocytes and monocytic intermediates, while reducing neutrophils and epithelial cells. Co-inhibition of TGF-β and PD-L1 signaling further enhances cytotoxic CD8+T cells and upregulates innate immune response and interferon gene signatures. However, simultaneous upregulation of cancer-related metabolic genes correlated with limited control of tumor burden and/or progression despite combination treatment. Our study illustrates the importance of using GEMMs to predict better immunotherapies for mCRC

First-person narratives around sexuality in residential healthcare settings: a meta-ethnographic synthesis

The aim of this review is to identify, critically appraise, and synthesise the existing literature exploring adults’ narratives around sexuality within residential healthcare settings from a first-person perspective. A systematic literature review was undertaken. Six databases were searched. A meta-ethnographic approach was used to synthesise studies’ findings. Thirteen studies using qualitative methodology that met the inclusion criteria were identified. The synthesis revealed six key themes: how service users define sexuality, sexuality as something not to be discussed (“privates are private”), sexuality as a separate aspect of the self (“sectionality”), hopes and fears for the future, the impact of the environment (“physicality of being physical”), and adapted sexuality. The studies included were of varying quality. Sexuality remains an important aspect for many residents, yet is rarely noted or discussed with them by healthcare staff. The residential healthcare environment presents implicit and explicit barriers to sexuality expression, causing residents to adapt how they experience their sexuality. Findings from this review highlight the importance of considering service users’ perspectives, and the need for open communication between residents and practitioners to facilitate care provision that acknowledges the barriers of the environment on sexuality and considers the person beyond the presenting illness

Does the engineering culture in UK higher education advance women’s careers?

Current research suggests that increases in the number of women studying engineering and related courses have not been matched by a similar increase in women engineering professionals. This suggests that although women are attracted to engineering, their experiences in higher education (HE) discourage them from pursuing their chosen career path. The paper explores whether the masculine culture of the engineering sector permeates the culture and curriculum in engineering HE, and if it does, what impact this has on women engineering students. This is achieved through semi-structured, qualitative interviews with a range of female engineering students from both the pre and post 1992 university sectors. Findings indicate that while women are not deterred from pursuing their chosen engineering career, the culture and structure of the engineering education system has been designed for a male audience. This suggests that engineering HE does not benefit most female students to the same extent as male students. It is recommended that HE engineering must review its structure, culture, practices and curriculum if it is to retain female engineering graduates and to attract more women into the sector. This paper fulfils an identified gap in research on women in engineering and will be of interest to university engineering departments and faculties and the Engineering Council, as well as to those in the fields of social policy, education and equal opportunities