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IntroductionClinical data suggest that over 70% of patients with Type 2 diabetes mellitus (T2DM) will die of cardiovascular diseases (CVD). T2DM patients with saphenous vein coronary artery bypass grafts are also prone to vein graft failure within 10 years, a phenomenon which arises from alterations in human saphenous vein smooth muscle cell (HSV-SMC) phenotype that trigger vascular thickening and re-modelling. T2DM involves metabolic dysfunction and chronic inflammation, manifested as increased levels of circulating pro-inflammatory cytokines including IL-1 and IL-6, and increased migration and proliferation of SMCs in response to mitogens such PDGF. However, the relationship between these phenomena and their contribution to HSV re-modelling responsible for vein graft failure remain unclear. Hence, our aim in this study was to evaluate the metabolic responses of HSV-SMCs from T2DM versus non-diabetic patients in response to pro-inflammatory cytokine IL-6 and mitogen PDGF.MethodsHSV-SMCs were explanted from surplus HSV tissues from T2DM and non-diabetic patients undergoing coronary artery bypass graft (CABG) surgery at the Cardiothroacic Surgery Department, Castle Hill Hospital, UK under NHRA ethical approval (NHS REC:15/NE/0138). SDS-PAGE and immunoblotting were used to assess IL-6 and PDGF-stimulated activation of STAT3 in HSV-SMCs by measuring phosphorylation of STAT3 on Tyr705 (p-STAT3). Mitochondrial function in HSV-SMCs was determined by measurement of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using the Agilent Seahorse XFp analyzer and sequential addition of modulators of respiration; oligomycin (1.5 μM), carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) (5 μM), and rotenone (5 μM) and antimycin A (5 μM).ResultsIn T2DM but not non-diabetic cells, IL-6 significantly elevated OCR and this was not associated with any significant difference in levels of IL-6-stimulated JAK-mediated STAT3 phosphorylation in cells from T2DM versus non-diabetic patients. However, the JAK1/2 inhibitor, ruxolitinib (0.1 μM) significantly abolished this IL-6-stimulated increase in OCR of T2DM. Also, IL-6 elevated ECAR in both T2DM and non-diabetic cells via a ruxolitinib-dependent mechanism. Same pattern was observed in response to HSV-SMC mitogen PDGF.ConclusionData from this study suggest that T2DM alters HSV-SMCs metabolic responses to proinflammatory stimulus IL-6 and mitogen PDGF. This alteration was abolished by ruxolitinib which suggests a JAK-mediated modulation of mitochondrial function of HSV-SMCs, hence a potential therapeutic target in T2DM-induced vein graft failure. Conflicts of interest: None

Pulmonary arterial hypertension (PAH) is a rare, devastating disease with no cure. Current treatment consists of a cocktail of vasodilators which relieve symptoms of PAH but do not treat the cause. Thus, there is a need for novel drugs that target the underlying pathological causes of PAH. PAH is a multi-factorial, but one key contributor is the pro-inflammatory cytokine IL-6 which stimulates pro-inflammatory and pro-angiogenic signalling mediated by the JAK/STAT pathway. One way in which IL-6 signalling via JAK/STAT is inhibited is via SOCS3 in a type of negative feedback loop whereby IL-6 induces transcription of SOCS3, which then attenuates further JAK/STAT signalling. SOCS3 can also be induced by cAMP. This is interesting as prostanoids, a type of drug used in the treatment of PAH due to its vasodilator effects and the only type to show any efficacy improving the life expectancy of PAH patients, acts by mobilising cAMP. Thus, prostanoid stimulation of cAMP could potentially limit IL-6 signalling via the induction of SOCS3. This is a novel mechanism of prostanoids which has not previously been considered. This study investigated the capability of prostanoids to limit the pro-inflammatory/pro-angiogenic effects of IL-6 that enable PAH to develop. Initial experiments confirmed that vascular endothelial cells responded to prostanoids which increased SOCS3 and limited IL-6 signalling activity. Further experiments utilising SOCS3 KO endothelial cell models demonstrated prostanoid inhibition of IL-6 signalling was due in part to SOCS3. In conclusion, this project has confirmed that prostanoids do limit the pro-inflammatory effects induced by IL-6 and that this is in part due to SOCS3. Although the exact mechanism is yet to be discovered, it will be beneficial in the treatment of PAH as it provides currently unexploited drug targets which can be considered for future PAH therapies.

Bird genomes are the smallest among amniotes, but remain challenging to assemble due to their structural complexity. This study presents the first fully phased, diploid, telomere-to-telomere (T2T) reference genome for the zebra finch ( ), a model organism for neuroscience and evolutionary genomics. Combining multiple sequencing strategies resulted in closing nearly all gaps, adding ~90 Mbp of previously missing sequence (7.8%). This includes T2T assemblies for all microchromosomes, including dot chromosomes, and the previously almost entirely missing chr16. The T2T genome is comprehensively annotated for genes, repeats, structural variants, and long-read methylation calls. Complete centromeric structures were assembled and annotated along with kinetochore binding sites. Relative to the previous high-quality reference of the Vertebrate Genomes Project, 2,778 (8.51%) previously unassembled or unannotated genes were identified, of which 9% overlap with segmental duplications. This first complete genome of a songbird, now the new public reference, illuminates avian genome architecture and function.

Glucose-driven mitochondrial dysfunction has been proposed to promote vascular cell proliferation and migration events responsible for saphenous vein graft failure (VGF) following bypass surgery. However, it is unclear how type 2 diabetes mellitus (T2DM) impacts mitochondrial function in human saphenous vein smooth muscle cells (HSVSMCs) responsible for the maladaptive remodelling responsible for VGF. Therefore, identifying and targeting the signalling pathways involved could offer new therapeutic options to limit VGF. Our aim was to identify signalling pathways that mediate any mitochondrial dysfunction in HSVSMCs in vitro and assess the impact of T2DM. HSVSMCs explanted from surplus HSV tissues from consenting T2DM and non-diabetic patients undergoing coronary artery bypass graft surgery were treated with known activators and inhibitors of the JAK/STAT and MAPK/ERK pathways. Following this, real-time oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) measures of mitochondrial function were then determined. Our findings revealed that both IL-6/sIL-6Rα trans-signalling complexes and PDGF-BB significantly increased OCR in HSVSMCs from T2DM patients but not non-diabetic controls. Meanwhile, only PDGF-BB increased ECAR in HSVSMCs from T2DM patients but not non-diabetic controls. The observed increases in OCR and ECAR were abolished by JAK1/2-selective inhibitor ruxolitinib. Furthermore, thrombin caused a significant increase in OCR specifically in HSVSMCs from T2DM patients, and this was abolished by MEK1/2-selective inhibitor trametinib. Both ruxolitinib and trametinib significantly reduced basal OCR and ECAR in HSVSMCs from both T2DM and non-diabetic patients. Together, these findings demonstrate a JAK/STAT- and MAPK/ERK-mediated regulation of mitochondrial function in HSVSMCs. As such, they represent potential targets for regulation of HSVSMC function that can be explored for drug development to limit saphenous VGF in T2DM.

Primordial germ cells (PGCs) are germline stem cells that develop into sperm or egg cells and are valuable for avian biobanking and the propagation of donor-derived offspring. However, in non-poultry birds the long-term maintenance and self-renewal of PGCs in vitro remains challenging. This limitation hinders biobanking in other avian clades, particularly in the zebra finch and other songbirds that uniquely possess a germline restricted chromosome (GRC). Here, we generated and compared short-term cultures of chicken and zebra finch PGCs from the embryonic gonads or blood, as well as established long-term cultures of chicken PGCs. Using single-cell RNA sequencing, we found that the transcriptome profile of long-term chicken gonadal cultures were exclusively PGCs, whereas the short-term chicken and zebra finch cultures represented a heterogeneous mixture of cell types. The zebra finch culture further included rapidly differentiating PGCs, as well as a germ cell type not previously identified in the embryonic songbird gonad. Although zebra finch short-term gonadal cultures did not yield robust long-term PGC cultures, short-term cultured PGCs were able to integrate into host zebra finch gonads after injection into the dorsal aorta, contribute to gametic populations in adult chimeras, and give rise to phenotypically- and genomically-validated offspring. This study provides a foundation for using short-term gonadal cultures to derive donor and transgenic offspring in songbirds and further explore the unique developmental genetics of PGCs across the avian clade. Beyond poultry, the long-term culture of self-renewing primordial germ cells (PGCs) remains a challenge. Here, we compare the cell population heterogeneity and reproductive viability of gonadal cultures for the zebra finch, a songbird model of vocal learning, with established chicken PGC protocols. Using single-cell RNA sequencing, we identify the rapid differentiation of zebra finch gonadal germ cells in vitro, including germline identities not previously noted in the embryonic gonad. In comparison, these differentiated cell profiles were also found in zebra finch blood PGC culture conditions, but not identified in short- or long-term chicken PGC cultures. Host embryo injections of these short-term zebra finch gonadal cultures resulted in germline chimeric animals, but at lower rates of gonadal reconstitution compared to chicken. Nonetheless, these cultures allowed for the derivation of zebra finch germline chimeras that yield phenotypically- and genomically-validated offspring from cultured PGCs.

Reviews the health consequences of cigar smoking and the effectiveness of comprehensive bans on tobacco product advertising and promotion in reducing the prevalence of smoking of tobacco products. Explains NZ's tobacco control strategy. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.

The effects of concanavalin A (ConA), a glucose/mannose-specific lectin from jackbean (Canavalia ensiformis), on insect crop pests from two different orders, Lepidoptera and Homoptera, were investigated. When fed to larvae of tomato moth (Lacanobia oleracea) at a range of concentrations (0.02–2.0% of total protein) in artificial diet, ConA decreased survival, with up to 90% mortality observed at the highest dose level, and retarded development, but had only a small effect on larval weight. When fed to peach-potato aphids (Myzus persicae) at a range of concentrations (1–9μM) in liquid artificial diet, ConA reduced aphid size by up to 30%, retarded development to maturity, and reduced fecundity (production of offspring) by >35%, but had little effect on survival. With both insects, there was a poor correlation between lectin dose and the quantitative effect. Constitutive expression of ConA in transgenic potatoes driven by the CaMV 35S promoter resulted in the protein accumulating to levels lower than predicted, possibly due to potato not being able to adequately reproduce the post-translational processing of this lectin which occurs in jackbean. However, the expressed lectin was functionally active as a haemagglutinin. Bioassay of L. oleracea larvae on ConA-expressing potato plants showed that the lectin retarded larval development, and decreased larval weights by >45%, but had no significant effect on survival. It also decreased consumption of plant tissue by the larvae. In agreement with the diet bioassay results, ConA-expressing potatoes decreased the fecundity of M. persicae by up to 45%. ConA thus has potential as a protective agent against insect pests in transgenic crops.

Durham reviews Disabling Globalization: Places of Power in Post Apartheid South Africa by Gillian Hart.