• MiR-486-3p and MiR-938—Important Inhibitors of Pacemaking Ion Channels and/or Markers of Immune Cells

      Aminu, Abimbola J; email: abimbola.akerele@postgrad.manchester.ac.uk; Petkova, Maria; email: petkova4656@gmail.com; Chen, Weixuan; orcid: 0000-0002-6857-0080; email: weixuan.chen@postgrad.manchester.ac.uk; Yin, Zeyuan; orcid: 0000-0001-7696-6985; email: zeyuan.yin@postgrad.manchester.ac.uk; Kuzmin, Vlad S; email: ku290381@gmail.com; Atkinson, Andrew J; orcid: 0000-0003-2017-0747; email: andrew.atkinson-2@manchester.ac.uk; Dobrzynski, Halina; orcid: 0000-0003-4754-5975; email: halina.dobrzynski@manchester.ac.uk (MDPI, 2021-12-01)
      The sinus node (SN) is the heart’s primary pacemaker and has a unique expression of pacemaking ion channels and immune cell markers. The role of microribonucleic acids (miRNAs) in control of ion channels and immune function of the sinus node is not well understood. We have recently shown that hsa-miR-486-3p downregulates the main pacemaking channel HCN4 in the SN. In addition, we recently demonstrated that immune cells are significantly more abundant in the SN compared to the right atrium. The aim of this study was to validate the previously predicted interactions between miRNAs and mRNAs of key Ca2+ ion channels (involved in peacemaking) and mRNA of TPSAB1—(a mast cells marker) using luciferase assay. We now show that miR-486 significantly downregulates Cav1.3, Cav3.1, and TPSAB1-mediated luciferase activity, while miR-938 significantly downregulates only TPSAB1-mediated luciferase activity. This makes miR-486-3p a potential therapeutic target in the treatment of SN dysfunctions.
    • Dryland dunes and other dryland environmental archives as proxies for Late Quaternary stratigraphy and environmental and climate change in southern Africa

      Stone, A.; email: abi.stone@manchester.ac.uk (Geological Society of South Africa, 2021-12-01)
      Abstract The Namib Desert and the Kalahari constitute the drylands of southern Africa, with the current relatively humid portions of the latter having experienced periodically drier conditions during the Late Quaternary. This study explores the range of dryland archives and proxies available for the past ~190 ka. These include classic dryland geomorphological proxies, such as sand dunes, as well as water-lain sediments within former lakes and ephemeral fluvial systems, lake shorelines, sand ramps, water-lain calcrete and tufa sediments at the interface of surface hydrological and hydrogeological, speleothems and groundwater hydrogeological records, and hyrax middens. Palaeoenvironmental evidence can also be contained within geoarchaeological archives in caves, overhangs and rockshelters. This integration of records is undertaken with the aim of identifying a (or a number of) terrestrial regional chronostratigraphic framework(s) for this time period within southern Africa, because this is missing from the Quaternary stratigraphy lexicon. Owing to a lack of long, near-continuous terrestrial sequences in these drylands, the correspondence between nearby terrestrial records are explored as a basis for parasequences to build this chronostratigraphy. Recognising the modern climatological diversity across the subcontinent, four broad spatial subdivisions are used to explore potential sub-regional parasequences, which capture current climatic gradients, including the hyper-arid west coast and the decrease in aridity from the southwest Kalahari toward the north and east. These are the Namib Desert, the northern Kalahari, the southern Kalahari and the eastern fringes of the southern Kalahari. Terrestrial chronostratigraphies must start from premise that climate-driven environmental shifts may have occurred independently to those in other terrestrial locations and may be diachronous compared to the marine oxygen isotope stratigraphy (MIS), which serves as a global-scale master climatostratigraphy relating to global ice volume. The fragmented nature of preserved evidence means that we are still some way from producing unambiguous parasequences. There is however, a rich record to consider, compile and compare, within which seven broad wetter intervals are identified, with breaks between these inferred to be relatively drier, and some also have proxy evidence for drying. The onset and cessation of these wetter intervals does not align with MIS: they occur with greater frequency, but not with regular periodicity. Precession-paced insolation forcing is often invoked as a key control on southern African climate, but this does not explain the pacing of all of the identified events. Overall, the pattern is complex with some corresponding wetter intervals across space and others with opposing west-east trends. The evidence for drying over the past 10 ka is pronounced in the west (Namib Desert), with ephemerally wet conditions in the south (southern Kalahari). The patterns identified here provide a framework to be scrutinised and to inspire refinements to proposed terrestrial chronostratigraphies for southern Africa. Considering changes across this large geographic area also highlights the complexity in environmental responses across space as we continue to test a range of hypotheses about the nature of climatic forcing in this region.
    • Engagement with consumer smartwatches for tracking symptoms of individuals living with multiple long-term conditions (multimorbidity): A longitudinal observational study

      Ali, Syed Mustafa; orcid: 0000-0001-9393-9049; email: syedmustafa.ali@manchester.ac.uk; Selby, David A; Khalid, Kazi; Dempsey, Katherine; Mackey, Elaine; Small, Nicola; van der Veer, Sabine N; McMillan, Brian; orcid: 0000-0002-0683-3877; Bower, Peter; Brown, Benjamin; et al. (SAGE Publications, 2021-11-30)
      Introduction: People living with multiple long-term conditions (multimorbidity) (MLTC-M) experience an accumulating combination of different symptoms. It has been suggested that these symptoms can be tracked longitudinally using consumer technology, such as smartphones and wearable devices. Aim: The aim of this study was to investigate longitudinal user engagement with a smartwatch application, collecting survey questions and active tasks over 90 days, in people living with MLTC-M. Methods: ‘Watch Your Steps’ was a prospective observational study, administering multiple questions and active tasks over 90 days. Adults with more than one clinician-diagnosed long-term conditions were loaned Fossil® Sport smartwatches, pre-loaded with the study app. Around 20 questions were prompted per day. Daily completion rates were calculated to describe engagement patterns over time, and to explore how these varied by patient characteristics and question type. Results: Fifty three people with MLTC-M took part in the study. Around half were male ( = 26; 49%) and the majority had a white ethnic background (n = 45; 85%). About a third of participants engaged with the smartwatch app nearly every day. The overall completion rate of symptom questions was 45% inter-quartile range (IQR 23–67%) across all study participants. Older patients and those with greater MLTC-M were more engaged, although engagement was not significantly different between genders. Conclusion: It was feasible for people living with MLTC-M to report multiple symptoms per day over 3 months. User engagement appeared as good as other mobile health studies that recruited people with single health conditions, despite the higher daily data entry burden.
    • Daily electrical activity in the master circadian clock of a diurnal mammal

      senior_editor: Dulac, Catherine; editor: Tessmar-Raible, Kristin; Bano-Otalora, Beatriz; orcid: 0000-0003-4694-9943; Moye, Matthew J; Brown, Timothy; Lucas, Robert J; orcid: 0000-0002-1088-8029; email: robert.lucas@manchester.ac.uk; Diekman, Casey O; orcid: 0000-0002-4711-1395; email: diekman@njit.edu; Belle, Mino DC; orcid: 0000-0002-4917-957X; email: M.D.C.Belle@exeter.ac.uk (eLife Sciences Publications, Ltd, 2021-11-30)
      Circadian rhythms in mammals are orchestrated by a central clock within the suprachiasmatic nuclei (SCN). Our understanding of the electrophysiological basis of SCN activity comes overwhelmingly from a small number of nocturnal rodent species, and the extent to which these are retained in day-active animals remains unclear. Here, we recorded the spontaneous and evoked electrical activity of single SCN neurons in the diurnal rodent Rhabdomys pumilio, and developed cutting-edge data assimilation and mathematical modeling approaches to uncover the underlying ionic mechanisms. As in nocturnal rodents, R. pumilio SCN neurons were more excited during daytime hours. By contrast, the evoked activity of R. pumilio neurons included a prominent suppressive response that is not present in the SCN of nocturnal rodents. Our modeling revealed and subsequent experiments confirmed transient subthreshold A-type potassium channels as the primary determinant of this response, and suggest a key role for this ionic mechanism in optimizing SCN function to accommodate R. pumilio’s diurnal niche.
    • High-energy synchrotron X-ray tomography coupled with digital image correlation highlights likely failure points inside ITER toroidal field conductors

      Warr, Ryan; Jewell, Matthew C.; Mitchell, Neil; Rack, Alexander; Swanson, Jack; Tronza, Vladimir; Cernik, Robert; email: b.cernik@manchester.ac.uk (Nature Publishing Group UK, 2021-11-30)
      Abstract: Two sections of heat-treated (HT) and non-heat-treated (NHT) Cable-in-Conduit Conductor (CICC) of a design similar to the ITER tokomak have been imaged using very high energy X-ray tomography at the ESRF beamline ID19. The sample images were collected at four temperatures down to 77 K. These results showed a greater degree of movement, bundle distortion and touching strands in the NHT sample. The HT sample showed non-linear movements with temperature especially close to 77 K; increasing non-circularity of the superconducting fibre bundles towards the periphery of the CICC, and touching bundles throughout the CICC. The images have highlighted where future design might improve potential weakness, in particular at the outer perimeters of the conductor and the individual sub-cable, ‘petal’ wraps.
    • The Differences in the Prevalence of Cardiovascular Disease, Its Risk Factors, and Achievement of Therapeutic Goals among Urban and Rural Primary Care Patients in Poland: Results from the LIPIDOGRAM 2015 Study

      Studziński, Krzysztof; orcid: 0000-0002-2486-4212; email: krzysztof.studzinski@uj.edu.pl; Tomasik, Tomasz; orcid: 0000-0002-9109-4174; email: mmtomasi@cyf-kr.edu.pl; Windak, Adam; email: mmwindak@cyf-kr.edu.pl; Banach, Maciej; email: maciejbanach77@gmail.com; Wójtowicz, Ewa; email: ewa.woj@poczta.onet.pl; Mastej, Mirosław; email: miroslaw@mastej.pl; Tomaszewski, Maciej; email: maciej.tomaszewski@manchester.ac.uk; Mikhailidis, Dimitri P.; email: mikhailidis@aol.com; Toth, Peter P.; email: peter.toth@cghmc.com; Catapano, Alberico; orcid: 0000-0002-7593-2094; email: alberico.catapano@unimi.it; et al. (MDPI, 2021-11-30)
      A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the years 2015 and 2016. A total of 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices. The prevalence of hypertension, diabetes mellitus, dyslipidaemia, and CVD were similar in urban and rural areas (49.5 vs. 49.4%; 13.7 vs. 13.1%; 84.2 vs. 85.2%; 14.4 vs. 14.2%, respectively). The prevalence of obesity (32.3 vs. 37.5%, p 0.01) and excessive waist circumference (77.5 vs. 80.7%, p 0.01), as well as abdominal obesity (p = 43.2 vs. 46.4%, p 0.01), were higher in rural areas in both genders. Mean levels of LDL-C (128 vs. 130 mg/dL, p = 0.04) and non-HDL-C (147 vs. 148 mg/dL, p = 0.03) were slightly higher in rural populations. Altogether, 14.3% of patients with CVD from urban areas and 11.3% from rural areas reached LDL 70 mg/dL (p = 0.04). There were no important differences in the prevalence of hypertension, diabetes, dyslipidaemia, and CVD, or in mean levels of blood pressure, cholesterol fractions, glucose, and HbA1c between Polish urban and rural primary care patient populations. A high proportion of patients in cities and an even-higher proportion in rural areas did not reach the recommended targets for blood pressure, LDL-C, and HbA1c, indicating the need for novel CVD-prevention programs.
    • Why do plasmids manipulate the expression of bacterial phenotypes?

      Billane, Kathryn; Harrison, Ellie; orcid: 0000-0002-2050-4631; Cameron, Duncan; Brockhurst, Michael A.; orcid: 0000-0003-0362-820X; email: michael.brockhurst@manchester.ac.uk (The Royal Society, 2021-11-29)
      Conjugative plasmids play an important role in bacterial evolution by transferring niche-adaptive traits between lineages, thus driving adaptation and genome diversification. It is increasingly clear, however, that in addition to this evolutionary role, plasmids also manipulate the expression of a broad range of bacterial phenotypes. In this review, we argue that the effects that plasmids have on the expression of bacterial phenotypes may often represent plasmid adaptations, rather than mere deleterious side effects. We begin by summarizing findings from untargeted omics analyses, which give a picture of the global effects of plasmid acquisition on host cells. Thereafter, because many plasmids are capable of both vertical and horizontal transmission, we distinguish plasmid-mediated phenotypic effects into two main classes based upon their potential fitness benefit to plasmids: (i) those that promote the competitiveness of the host cell in a given niche and thereby increase plasmid vertical transmission, and (ii) those that promote plasmid conjugation and thereby increase plasmid horizontal transmission. Far from being mere vehicles for gene exchange, we propose that plasmids often act as sophisticated genetic parasites capable of manipulating their bacterial hosts for their own benefit. This article is part of the theme issue ‘The secret lives of microbial mobile genetic elements’.
    • Inactivity of Peptidase ClpP Causes Primary Accumulation of Mitochondrial Disaggregase ClpX with Its Interacting Nucleoid Proteins, and of mtDNA

      Key, Jana; email: jana.key88@gmail.com; Torres-Odio, Sylvia; email: torres.odio@exchange.tamu.edu; Bach, Nina C.; email: nina.bach@tum.de; Gispert, Suzana; email: Gispert-Sanchez@em.uni-frankfurt.de; Koepf, Gabriele; email: Gabriele.Koepf@kgu.de; Reichlmeir, Marina; orcid: 0000-0002-1551-6865; email: Marina.Reichlmeir@gmail.com; West, A. Phillip; orcid: 0000-0003-2884-6895; email: awest@tamu.edu; Prokisch, Holger; orcid: 0000-0003-2379-6286; email: prokisch@helmholtz-muenchen.de; Freisinger, Peter; orcid: 0000-0003-1675-9372; email: Freisinger_P@klin-rt.de; Newman, William G.; email: william.newman@manchester.ac.uk; et al. (MDPI, 2021-11-29)
      Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.
    • MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

      Baxter, Diana E.; orcid: 0000-0001-8830-6802; email: diana.baxter@cruk.manchester.ac.uk; Allinson, Lisa M.; email: lisa.allinson@newcastle.ac.uk; Al Amri, Waleed S.; orcid: 0000-0002-2669-7577; email: waleedsaid.alamri@moh.gov.om; Poulter, James A.; orcid: 0000-0003-2048-5693; email: J.A.Poulter@leeds.ac.uk; Pramanik, Arindam; email: A.Pramanik@leeds.ac.uk; Thorne, James L.; orcid: 0000-0002-3037-8528; email: J.L.Thorne@leeds.ac.uk; Verghese, Eldo T.; email: eldoverghese@nhs.net; Hughes, Thomas A.; orcid: 0000-0003-1169-3386; email: t.hughes@leeds.ac.uk (MDPI, 2021-11-28)
      Background: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation. Through this comparison, we aimed to identify microRNAs associated with chemoresistance, define microRNA target genes, and assess targets as predictors of chemotherapy response. Methods: cancer cells were laser microdissected from matched breast cancer tissues pre- and post-chemotherapy from estrogen receptor positive/HER2 negative breast cancers showing partial responses to epirubicin/cyclophosphamide chemotherapy (n = 5). MicroRNA expression was profiled using qPCR arrays. MicroRNA/mRNA expression was manipulated in estrogen receptor positive/HER2 negative breast cancer cell lines (MCF7 and MDA-MB-175 cells) with mimics, inhibitors or siRNAs, and chemoresponse was assessed using MTT and colony forming survival assays. MicroRNA targets were identified by RNA-sequencing of microRNA mimic pull-downs, and comparison of these with mRNAs containing predicted microRNA binding sites. Survival correlations were tested using the METABRIC expression dataset (n = 1979). Results: miR-195 and miR-26b were consistently up-regulated after therapy, and changes in their expression in cell lines caused significant differences in chemotherapy sensitivity, in accordance with up-regulation driving resistance. SEMA6D was defined and confirmed as a target of the microRNAs. Reduced SEMA6D expression was significantly associated with chemoresistance, in accordance with SEMA6D being a down-stream effector of the microRNAs. Finally, low SEMA6D expression in breast cancers was significantly associated with poor survival after chemotherapy, but not after other therapies. Conclusions: microRNAs and their targets influence chemoresponse, allowing the identification of SEMA6D as a predictive marker for chemotherapy response that could be used to direct therapy or as a target in chemosensitisation strategies.
    • Functionalized Tris(anilido)triazacyclononanes as Hexadentate Ligands for the Encapsulation of U(III), U(IV) and La(III) Cations

      Formanuik, Alasdair; email: aformanuik@outlook.com; Ortu, Fabrizio; orcid: 0000-0002-1743-8338; email: fabrizio.ortu@leicester.ac.uk; Vitorica-Yrezabal, Iñigo J.; orcid: 0000-0001-8806-150X; email: inigo.vitorica@manchester.ac.uk; Tuna, Floriana; email: Floriana.Tuna@manchester.ac.uk; McInnes, Eric J. L.; email: eric.mcinnes@manchester.ac.uk; Natrajan, Louise S.; orcid: 0000-0002-9451-3557; email: louise.natrajan@manchester.ac.uk; Mills, David P.; orcid: 0000-0003-1575-7754; email: david.mills@manchester.ac.uk (MDPI, 2021-11-28)
      Tripodal multidentate ligands have become increasingly popular in f-element chemistry for stabilizing unusual bonding motifs and supporting small molecule activation processes. The steric and electronic effects of ligand donor atom substituents have proved crucial in both of these applications. In this study we functionalized the previously reported tris-anilide ligand {tacn(SiMe2NPh)3} (tacn = 1,3,7-triazacyclononane) to incorporate substituted aromatic rings, with the aim of modifying f-element complex solubility and ligand steric effects. We report the synthesis of two proligands, {tacn(SiMe2NHAr)3} (Ar = C6H3Me2-3,5 or C6H4Me-4), and their respective group 1 transfer agents—{tacn(SiMe2NKAr)3}, M(III) complexes [M{tacn(SiMe2NAr)3}] for M = La and U, and U(IV) complexes [M{tacn(SiMe2NAr)3}(Cl)]. These compounds were characterized by multinuclear NMR and FTIR spectroscopy and elemental analysis. The paramagnetic uranium complexes were also characterized by solid state magnetic measurements and UV/Vis/NIR spectroscopy. U(III) complexes were additionally studied by EPR spectroscopy. The solid state structures of all f-block complexes were authenticated by single-crystal X-ray diffraction (XRD), together with a minor byproduct [U{tacn(SiMe2NC6H4Me-4)3}(I)]. Comparisons of the characterization data of our f-element complexes with similar literature examples containing the {tacn(SiMe2NPh)3} ligand set showed minor changes in physicochemical properties resulting from the different aromatic ring substitution patterns we investigated.
    • Co-designing new tools for collecting, analysing and presenting patient experience data in NHS services: working in partnership with patients and carers

      Small, Nicola; orcid: 0000-0002-7879-7967; email: nicola.small@manchester.ac.uk; Ong, Bie Nio; orcid: 0000-0001-8138-8139; Lewis, Annmarie; Allen, Dawn; Bagshaw, Nigel; Nahar, Papreen; orcid: 0000-0002-5817-8093; Sanders, Caroline; orcid: 0000-0002-0539-928X; Hodgson, Damian; Dehghan, Azad; Sharp, Charlotte; et al. (BioMed Central, 2021-11-27)
      Abstract: Background: The way we collect and use patient experience data is vital to optimise the quality and safety of health services. Yet, some patients and carers do not give feedback because of the limited ways data is collected, analysed and presented. In this study, we worked together with researchers, staff, patient and carer participants, and patient and public involvement and engagement (PPIE) contributors, to co-design new tools for the collection and use of patient experience data in multiple health settings. This paper outlines how the range of PPIE and research activities enabled the co-design of new tools to collect patient experience data. Methods: Eight public contributors represented a range of relevant patient and carer experiences in specialist services with varied levels of PPIE experience, and eleven members of Patient and Participation Groups (PPGs) from two general practices formed our PPIE group at the start of the study. Slide sets were used to trigger co-design discussions with staff, patient and carer research participants, and PPIE contributors. Feedback from PPIE contributors alongside verbatim quotes from staff, patient and carer research participants is presented in relation to the themes from the research data. Results: PPIE insights from four themes: capturing experience data; adopting digital or non-digital tools; ensuring privacy and confidentiality; and co-design of a suite of new tools with guidance, informed joint decisions on the shaping of the tools and how these were implemented. Our PPIE contributors took different roles during co-design and testing of the new tools, which supported co-production of the study. Conclusions: Our experiences of developing multiple components of PPIE work for this complex study demonstrates the importance of tailoring PPIE to suit different settings, and to maximise individual strengths and capacity. Our study shows the value of bringing diverse experiences together, putting patients and carers at the heart of improving NHS services, and a shared approach to managing involvement in co-design, with the effects shown through the research process, outcomes and the partnership. We reflect on how we worked together to create a supportive environment when unforeseen challenges emerged (such as, sudden bereavement).
    • ABO Blood Groups Do Not Predict Schistosoma mansoni Infection Profiles in Highly Endemic Villages of Uganda

      Francoeur, Rachel; orcid: 0000-0003-1860-4374; email: r.francoeur@chester.ac.uk; Atuhaire, Alon; orcid: ; email: aaronatuhaire@gmail.com; Arinaitwe, Moses; orcid: ; email: moses0772359814@gmail.com; Adriko, Moses; orcid: 0000-0001-9748-1207; email: adrikomoses@gmail.com; Ajambo, Diana; orcid: ; email:; Nankasi, Andrina; orcid: ; email: n1andrina@gmail.com; Babayan, Simon; orcid: ; email: simon.babayan@glasgow.ac.uk; Lamberton, Poppy; orcid: 0000-0003-1048-6318; email: poppy.lamberton@glasgow.ac.uk (MDPI, 2021-11-27)
      Schistosoma mansoni is a parasite which causes significant public-health issues, with over 240 million people infected globally. In Uganda alone, approximately 11.6 million people are affected. Despite over a decade of mass drug administration in this country, hyper-endemic hotspots persist, and individuals who are repeatedly heavily and rapidly reinfected are observed. Human blood-type antigens are known to play a role in the risk of infection for a variety of diseases, due to cross-reactivity between host antibodies and pathogenic antigens. There have been conflicting results on the effect of blood type on schistosomiasis infection and pathology. Moreover, the effect of blood type as a potential intrinsic host factor on S. mansoni prevalence, intensity, clearance, and reinfection dynamics and on co-infection risk remains unknown. Therefore, the epidemiological link between host blood type and S. mansoni infection dynamics was assessed in three hyper-endemic communities in Uganda. Longitudinal data incorporating repeated pretreatment S. mansoni infection intensities and clearance rates were used to analyse associations between blood groups in school-aged children. Soil-transmitted helminth coinfection status and biometric parameters were incorporated in a generalised linear mixed regression model including age, gender, and body mass index (BMI), which have previously been established as significant factors influencing the prevalence and intensity of schistosomiasis. The analysis revealed no associations between blood type and S. mansoni prevalence, infection intensity, clearance, reinfection, or coinfection. Variations in infection profiles were significantly different between the villages, and egg burden significantly decreased with age. While blood type has proven to be a predictor of several diseases, the data collected in this study indicate that it does not play a significant role in S. mansoni infection burdens in these high-endemicity communities.
    • Renal hemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularized composite allograft—A preclinical study

      Stone, John P.; orcid: 0000-0001-9452-2843; Amin, Kavit R.; Geraghty, Abbey; Kerr, Jak; Shaw, Matthew; Dabare, Dilan; Wong, Jason K.; Brough, David; Entwistle, Timothy R.; Montero‐Fernandez, Angeles; et al. (2021-11-26)
      Abstract: Introduction: Recent experimental evidence suggests normothermic machine perfusion of the vascularized composite allograft results in improved preservation compared to static cold storage, with less reperfusion injury in the immediate post‐operative period. However, metabolic acidosis is a common feature of vascularized composite allograft perfusion, primarily due to the inability to process metabolic by‐products. We evaluated the impact of combined limb‐kidney perfusion on markers of metabolic acidosis and inflammation in a porcine model. Methods: Ten paired pig forelimbs were used for this study, grouped as either limb‐only (LO, n = 5) perfusion, or limb‐kidney (LK, n = 5) perfusion. Infrared thermal imaging was used to determine homogeneity of perfusion. Lactate, bicarbonate, base, pH, and electrolytes, along with an inflammatory profile generated via the quantification of cytokines and cell‐free DNA in the perfusate were recorded. Results: The addition of a kidney to a limb perfusion circuit resulted in the rapid stabilization of lactate, bicarbonate, base, and pH. Conversely, the LO circuit became progressively acidotic, correlating in a significant increase in pro‐inflammatory cytokines. Global perfusion across the limb was more homogenous with LK compared to LO. Conclusion: The addition of a kidney during limb perfusion results in significant improvements in perfusate biochemistry, with no evidence of metabolic acidosis.
    • Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

      Ansari-Pour, Naser; orcid: 0000-0003-0908-0484; Zheng, Yonglan; orcid: 0000-0001-6597-7072; Yoshimatsu, Toshio F.; orcid: 0000-0003-2674-8159; Sanni, Ayodele; Ajani, Mustapha; orcid: 0000-0001-5758-5773; Reynier, Jean-Baptiste; Tapinos, Avraam; Pitt, Jason J.; Dentro, Stefan; Woodard, Anna; et al. (Nature Publishing Group UK, 2021-11-26)
      Abstract: Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.
    • Enclave-Reinforced Inequality during the COVID-19 Pandemic: Evidence from University Campus Lockdowns in Wuhan, China

      Sun, Cheng; orcid: 0000-0001-6505-821X; email: suncheng@hbue.edu.cn; Xiong, Yaxuan; email: xiongyaxuan@mail.hbue.edu.cn; Wu, Zhiqin; email: zhiqin.wu@manchester.ac.uk; Li, Jie; email: 18170049@mail.hbue.edu.cn (MDPI, 2021-11-26)
      The COVID-19 pandemic has impacted urban life and created spatial and social inequalities in cities. The impacts of lifting full lockdown restrictions once fast-spreading and community-acquired infection waves were under control are still not fully understood. This study aims to explore spatial inequality reinforced in the intervals between the waves of infection during the COVID-19 pandemic. Enclave-reinforced inequality resulting from enclave-based lockdown policies in Chinese cities was investigated through an analysis of the impacts of university campus enclave closures on the accessibility and crowdedness of urban green spaces. Using a modified two-step floating catchment area (2SFCA) and inversed 2SFCA (i2SFCA) method, accessibility and crowdedness were calculated and compared under two different scenarios. Additionally, the Lorenz curve, Gini coefficient, and Theil index were used to measure and compare intra-city global and local inequalities under each scenario. The results indicate that the lockdown of university campus enclaves decreased the supply of urban green spaces. Campus closures not only exacerbated the unequal distribution of urban green space, but also reduced the inequality of crowdedness in urban parks due to increased crowdedness in parks near the closed enclaves. Moreover, both accessibility and crowdedness worsened when the calculations were weighted for population size and the total supply of green space. Enclave-based lockdown in cities reinforced spatial inequality, and it is highly complex and has multidimensional impacts on urban inequalities and environmental injustice which should be considered by urban planners and decision-makers hoping to create healthy, inclusive, resilient, and sustainable cities in the “new normal” of the COVID-19 pandemic.
    • Primary Skull Base Chondrosarcomas: A Systematic Review

      Palmisciano, Paolo; orcid: 0000-0003-0711-3975; email: paolo.palmisciano94@gmail.com; Haider, Ali S.; email: aralam09@gmail.com; Sabahi, Mohammadmahdi; orcid: 0000-0003-4640-226X; email: mmsabahi1996@gmail.com; Nwagwu, Chibueze D.; email: dominicnwagwu@gmail.com; Bin Alamer, Othman; orcid: 0000-0001-9365-4115; email: oabinalamer@gmail.com; Scalia, Gianluca; orcid: 0000-0002-9465-2506; email: gianluca.scalia@outlook.it; Umana, Giuseppe E.; orcid: 0000-0002-1573-431X; email: umana.nch@gmail.com; Cohen-Gadol, Aaron A.; orcid: 0000-0002-4946-1524; email: cohen@nsatlas.com; El Ahmadieh, Tarek Y.; orcid: 0000-0002-7122-4349; email: telahmadieh@gmail.com; Yu, Kenny; email: yuk2@mskcc.org; et al. (MDPI, 2021-11-26)
      Background: Primary skull base chondrosarcomas (SBCs) can severely affect patients’ quality of life. Surgical-resection and radiotherapy are feasible but may cause debilitating complications. We systematically reviewed the literature on primary SBCs. Methods: PubMed, EMBASE, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA guidelines to include studies of patients with primary SBCs. Clinical characteristics, management strategies, and treatment outcomes were analyzed. Results: We included 33 studies comprising 1307 patients. Primary SBCs mostly involved the middle-fossa (72.7%), infiltrating the cavernous-sinus in 42.4% of patients. Cranial-neuropathies were reported in 810 patients (62%). Surgical-resection (93.3%) was preferred over biopsy (6.6%). The most frequent open surgical approaches were frontotemporal-orbitozygomatic (17.6%) and pterional (11.9%), and 111 patients (21.3%) underwent endoscopic-endonasal resection. Post-surgical cerebrospinal-fluid leaks occurred in 36 patients (6.5%). Radiotherapy was delivered in 1018 patients (77.9%): photon-based (41.4%), proton-based (64.2%), and carbon-based (13.1%). Severe post-radiotherapy complications, mostly hypopituitarism (15.4%) and hearing loss (7.1%) were experienced by 251 patients (30.7%). Post-treatment symptom-improvement (46.7%) and reduced/stable tumor volumes (85.4%) showed no differences based on radiotherapy-protocols (p = 0.165; p = 0.062). Median follow-up was 67-months (range, 0.1−376). SBCs recurrences were reported in 211 cases (16.1%). The 5-year and 10-year progression-free survival rates were 84.3% and 67.4%, and overall survival rates were 94% and 84%. Conclusion: Surgical-resection and radiotherapy are effective treatments in primary SBCs, with acceptable complication rates and favorable local tumor control.
    • Bettina Hitzer, Krebs Fühlen: Eine Emotionsgeschichte des 20. Jahrhunderts

      Timmermann, Carsten; email: carsten.timmermann@manchester.ac.uk (Brill, 2021-11-26)
    • The effects of sex and handedness on masturbation laterality and other lateralized motor behaviours

      Rodway, Paul; orcid: 0000-0002-7667-6782; Thoma, Volker; orcid: 0000-0001-7766-4233; Schepman, Astrid; orcid: 0000-0002-7407-362X (Informa UK Limited, 2021-11-26)
    • The effect of hypoxia on PD-L1 expression in bladder cancer

      Smith, Vicky; email: victoria.smith-15@postgrad.manchester.ac.uk; Mukherjee, Debayan; Lunj, Sapna; Choudhury, Ananya; Hoskin, Peter; West, Catharine; Illidge, Tim (BioMed Central, 2021-11-25)
      Abstract: Introduction: Recent data has demonstrated that hypoxia drives an immunosuppressive tumour microenvironment (TME) via various mechanisms including hypoxia inducible factor (HIF)-dependent upregulation of programmed death ligand 1 (PD-L1). Both hypoxia and an immunosuppressive TME are targetable independent negative prognostic factors for bladder cancer. Therefore we sought to investigate whether hypoxia is associated with upregulation of PD-L1 in the disease. Materials and methods: Three human muscle-invasive bladder cancer cell lines (T24, J82, UMUC3) were cultured in normoxia (20% oxygen) or hypoxia (1 and 0.1% oxygen) for 24 h. Differences in PD-L1 expression were measured using Western blotting, quantitative polymerase chain reaction (qPCR) and flow cytometry (≥3 independent experiments). Statistical tests performed were unpaired t tests and ANOVA. For in silico work an hypoxia signature was used to apply hypoxia scores to muscle-invasive bladder cancers from a clinical trial (BCON; n = 142) and TCGA (n = 404). Analyses were carried out using R and RStudio and statistical tests performed were linear models and one-way ANOVA. Results: When T24 cells were seeded at < 70% confluence, there was decreased PD-L1 protein (p = 0.009) and mRNA (p < 0.001) expression after culture in 0.1% oxygen. PD-L1 protein expression decreased in both 0.1% oxygen and 1% oxygen in a panel of muscle-invasive bladder cancer cells: T24 (p = 0.009 and 0.001), J82 (p = 0.008 and 0.013) and UMUC3 (p = 0.003 and 0.289). Increasing seeding density decreased PD-L1 protein (p < 0.001) and mRNA (p = 0.001) expression in T24 cells grown in both 20 and 1% oxygen. Only when cells were 100% confluent, were PD-L1 protein and mRNA levels higher in 1% versus 20% oxygen (p = 0.056 and p = 0.037). In silico analyses showed a positive correlation between hypoxia signature scores and PD-L1 expression in both BCON (p = 0.003) and TCGA (p < 0.001) cohorts, and between hypoxia and IFNγ signature scores (p < 0.001 for both). Conclusion: Tumour hypoxia correlates with increased PD-L1 expression in patient derived bladder cancer tumours. In vitro PD-L1 expression was affected by cell density and decreased PD-L1 expression was observed after culture in hypoxia in muscle-invasive bladder cancer cell lines. As cell density has such an important effect on PD-L1 expression, it should be considered when investigating PD-L1 expression in vitro.
    • Gene editing enables rapid engineering of complex antibiotic assembly lines

      Thong, Wei Li; Zhang, Yingxin; Zhuo, Ying; Robins, Katherine J.; orcid: 0000-0001-5049-4246; Fyans, Joanna K.; Herbert, Abigail J.; Law, Brian J. C.; Micklefield, Jason; orcid: 0000-0001-8951-4873; email: jason.micklefield@manchester.ac.uk (Nature Publishing Group UK, 2021-11-25)
      Abstract: Re-engineering biosynthetic assembly lines, including nonribosomal peptide synthetases (NRPS) and related megasynthase enzymes, is a powerful route to new antibiotics and other bioactive natural products that are too complex for chemical synthesis. However, engineering megasynthases is very challenging using current methods. Here, we describe how CRISPR-Cas9 gene editing can be exploited to rapidly engineer one of the most complex megasynthase assembly lines in nature, the 2.0 MDa NRPS enzymes that deliver the lipopeptide antibiotic enduracidin. Gene editing was used to exchange subdomains within the NRPS, altering substrate selectivity, leading to ten new lipopeptide variants in good yields. In contrast, attempts to engineer the same NRPS using a conventional homologous recombination-mediated gene knockout and complementation approach resulted in only traces of new enduracidin variants. In addition to exchanging subdomains within the enduracidin NRPS, subdomains from a range of NRPS enzymes of diverse bacterial origins were also successfully utilized.