• Knowledge and the Fall in American Neo-Calvinism: Toward a Van Til–Plantinga Synthesis

      Békefi, Bálint; email: balint.bekefi@gmail.com (Brill, 2021-09-17)
      Abstract Cornelius Van Til and Alvin Plantinga represent two strands of American Protestant philosophical thought influenced by Dutch neo-Calvinism. This paper compares and synthetizes their models of knowledge in non-Christians given the noetic effects of sin and non-Christian worldview commitments. The paper argues that Van Til’s distinction between the partial realization of the antithesis in practice and its absolute nature in principle correlates with Plantinga’s insistence on prima facie–warranted common-sense beliefs and their ultimate defeasibility given certain metaphysical commitments. Van Til endorsed more radical claims than Plantinga on epistemic defeat in non-Christian worldviews, the status of the sensus divinitatis, and conceptual accuracy in knowledge of the world. Finally, an approach to the use of evidence in apologetics is developed based on the proposed synthesis. This approach seeks to make more room for evidence than is generally recognized in Van Tilianism, while remaining consistent with the founder’s principles.
    • The enduring effect of early life adversities on health trajectories.

      Webb, Roger T; email: roger.webb@manchester.ac.uk; John, Ann; Mytton, Julie (2021-09-29)
    • Distance, Time, Speed & Energy: A socio-political analysis of technologies of longer distance cycling

      Cox, Peter; orcid: 0000-0003-2374-3125 (University of Westminster Press, 2021-10-07)
      The basic laws of motion governing cycling are wellunderstood. Consideration of the variables of energy use in cycle travel areless frequent. The potentials of both aerodynamically efficient cycle designand the augmentation of human power with e-motors dramatically reconfigure whatwe understand as a cycle and as cycling. The prospect of increasing travel distance in regularjourneying, coupled with the logical application of augmentation (aerodynamicand/ or power), suggest a need to re-evaluate some of the ground expectationsapplied in design and planning for cycle travel if the cycles being designedfor do not fit the existing expectations of what a cycle is and how itperforms. Current e-bike performance is limited principally bynormative legislative intervention, not by the intrinsic potential of thetechnologies. Existing decisions as to what an e-bike can (and should) be, areshaped by the performance expectations of late 19th and early 20thcentury bicycle designs. Shaping modal shift for longer trips returns us tothink about the place of cycling travel time as a function of the relationshipbetween distance and speed. Increased speed allows for greater distance withouttime penalty. However, speed is itself governed by available energy, coupledwith the efficiency of use of that energy. Without entirely substituting humanpower, E-motors allow us to augment the human power available in differentways; Changes in cycle design (as us, for example, in velomobiles) allow us toincrease the efficiency of use of available power in overcoming resistance tomovementIdentifying the assemblage of cycle/cyclist as avariable, rather than a determinate object to be accommodated, raises difficultquestions for cycling provision, especially in relation to longer distancetravel.This paper takes an approach rooted in Actor NetworkTheory and developed through social practice analysis to explore theinteractions of people machines and spaces for longer distance travel. It paysparticular attention to the capacities and affordances of each of theseelements, especially in their interaction. Drawing on the capacities of already existingtechnologies of cycling and e-cycling, the paper focuses on the socialimplications of potentially problematic interactions. It argues that newdecisions will need to be made in regard to speed and distance in cycle traveland that the forging of regulations consequent on those fundamentals  will substantially shape the potentials andpossibilities of modal shift for longer distance cycle travel. What emerges isa politics of longer distance cycle, not simply a set of technical barriers andproblems.
    • Environmental Assessment of Latent Heat Thermal Energy Storage Technology System with Phase Change Material for Domestic Heating Applications

      Chocontá Bernal, Daniel; email: Daniel.chocontabernal@postgrad.manchester.ac.uk; Muñoz, Edmundo; orcid: 0000-0002-7258-6069; email: edmundo.munoz@unab.cl; Manente, Giovanni; orcid: 0000-0001-7134-8731; email: G.Manente@bham.ac.uk; Sciacovelli, Adriano; orcid: 0000-0001-9684-3122; email: a.sciacovelli@bham.ac.uk; Ameli, Hossein; orcid: 0000-0003-4056-9819; email: h.ameli14@imperial.ac.uk; Gallego-Schmid, Alejandro; email: alejandro.gallegoschmid@manchester.ac.uk (MDPI, 2021-10-13)
      The emissions generated by the space and water heating of UK homes need to be reduced to meet the goal of becoming carbon neutral by 2050. The combination of solar (S) collectors with latent heat thermal energy storage (LHTES) technologies with phase change materials (PCM) can potentially help to achieve this goal. However, there is limited understanding of the environmental sustainability of LHTES technologies from a full life cycle perspective. This study assesses for the first time 18 environmental impacts of a full S-LHTES-PCM system from a cradle to grave perspective and compares the results with the most common sources of heat in UK homes. The results show that the system’s main environmental hotspots are the solar collector, the PCM, the PCM tank, and the heat exchanger. The main cause of most of the impacts is the extensive consumption of electricity and heat during the production of raw materials for these components. The comparison with other sources of household heat (biomass, heat pump, and natural gas) indicates that the S-LHTES-PCM system generates the highest environmental impact in 11 of 18 categories. However, a sensitivity analysis based on the lifetime of the S-LHTES-PCM systems shows that, when the lifetime increases to 40 years, almost all the impacts are significantly reduced. In fact, a 40-year S-LHTES-PCM system has a lower global warming potential than natural gas.
    • Detection of MCM5 as a novel non-invasive aid for the diagnosis of endometrial and ovarian tumours

      Stockley, J.; Akhand, R.; Kennedy, A.; Nyberg, C.; Crosbie, E. J.; Edmondson, R. J.; orcid: 0000-0003-2553-4423; email: richard.edmondson@manchester.ac.uk (BioMed Central, 2020-10-15)
      Abstract: Background: MCM5 is a protein involved in DNA replication, facilitating cell proliferation. In normal epithelium MCM5 expression is restricted to the cells in the basal proliferative compartments, however in the presence of a tumour MCM5 positive cells are present at the surface epithelium and are shed into bodily fluids. The aim of this study was to determine the sensitivity of MCM5 as a biomarker for the detection of endometrial and ovarian cancer. Methods: Patients with known ovarian or endometrial cancers, or known benign gynaecological conditions, were enrolled. Informed consent was obtained prior to the collection of full void urine, and either a vaginal tampon (worn for 6–8 h), or a vaginal swab. Vaginal secretions were extracted from the tampon or swab, centrifuged and lysed. Urine samples were centrifuged and lysed. MCM5 levels were determined by MCM5-ELISA (Arquer Diagnostics Ltd). Results: 125 patients completed the study protocol, 41 patients had endometrial cancer, 26 ovarian cancer, and 58 benign controls. All patients provided a urine sample and either a tampon or vaginal swab sample. Urine MCM5 levels were higher in cancer patients than controls (p < 0.0001), there was no significant difference in levels between tampon samples or vaginal swab samples in cancer patients when compared to controls. Performance of MCM5 to discriminate cancer from benign disease was high with an area under the ROC curve of 0.83 for endometrial cancer and 0.68 for ovarian cancer. Using a cut off of 12 pg/mL, overall sensitivity for endometrial cancer was 87.8, and 61.5% for ovarian cancer with a specificity of 75.9%. Conclusions: MCM5 is a novel sensitive and specific biomarker for the detection of ovarian and endometrial tumours in urine samples, which is likely to have clinical utility as a diagnostic aid.
    • The Challenges of Measuring Informal Care Time: A Review of the Literature

      Urwin, Sean; orcid: 0000-0002-9084-8368; email: sean.urwin@manchester.ac.uk; Lau, Yiu-Shing; Grande, Gunn; Sutton, Matt (Springer International Publishing, 2021-07-29)
      Abstract: Economic evaluations increasingly include the value of informal care, for example, in terms of caregiver health effects or time costs. If an economic evaluation uses caregiving time costs, appropriate measurement of caregiving time is an important first step prior to its valuation. There is no comprehensive overview of the measurement challenges for caregiving time. In this literature review, we searched Medline, Embase, Econlit and Scopus to identify measurement issues and associated studies which reported informal care time that addressed them. The search identified 27 studies that addressed nine measurement issues. There is limited evidence on how to address these issues, although some have received relatively more attention, including incremental time (considered in 16 studies), time measurement method comparisons (six studies) and the inclusion of intangible tasks (four studies). Non-response (considered in only one study) and carer and recipient identification (two studies) were the most wide-reaching measurement concerns, as these determine who is identified as carers. There was no evidence on the consequences of these measurement challenges in terms of impacts on cost-effectiveness ratios and on the total cost of health conditions, which would be a crucial next step. Future research on these issues should consider a range of different settings, as informal care is highly heterogeneous. The measurement of informal care is key for its inclusion in economic evaluations but there is little consensus on how to appropriately measure this type of care.
    • The impact of COVID-19 on digital data practices in museums and art galleries in the UK and the US

      Noehrer, Lukas; orcid: 0000-0002-9167-0397; email: lukas.noehrer@manchester.ac.uk; Gilmore, Abigail; Jay, Caroline; Yehudi, Yo; orcid: 0000-0003-2705-1724 (Palgrave Macmillan UK, 2021-10-15)
      Abstract: The first quarter of 2020 heralded the beginning of an uncertain future for museums and galleries as the COVID-19 pandemic hit and the only means to stay ‘open’ was to turn towards the digital. In this paper, we investigate how the physical closure of museum buildings due to lockdown restrictions caused shockwaves within their digital strategies and changed their data practices potentially for good. We review the impact of COVID-19 on the museum sector, based on literature and desk research, with a focus on the implications for three museums and art galleries in the United Kingdom and the United States, and their mission, objectives, and digital data practices. We then present an analysis of ten qualitative interviews with expert witnesses working in the sector, representing different roles and types of institutions, undertaken between April and October 2020. Our research finds that digital engagement with museum content and practices around data in institutions have changed and that digital methods for organising and accessing collections for both staff and the general public have become more important. We present evidence that strategic preparedness influenced how well institutions were able to transition during closure and that metrics data became pivotal in understanding this novel situation. Increased engagement online changed traditional audience profiles, challenging museums to find ways of accommodating new forms of engagement in order to survive and thrive in the post-pandemic environment.
    • The Effect of Authigenic Clays on Fault Zone Permeability

      Farrell, N. J. C.; orcid: 0000-0002-8491-9094; email: natalie.farrell@manchester.ac.uk; Debenham, N.; Wilson, L.; Wilson, M. J.; Healy, D.; orcid: 0000-0003-2685-1498; King, R. C.; Holford, S. P.; orcid: 0000-0002-4524-8822; Taylor, C. W. (2021-10-15)
      Abstract: Clays are understood to form the majority of fluid‐flow barriers in faulted reservoirs and numerous fault gouge and fault seal studies have quantified the volumes of smeared and abraded clays create fluid‐flow barriers along fault surfaces. However, clay‐related permeability adjacent to the fault surface, including in the fault damage zone, has largely been neglected. Previous studies have shown the morphology and distribution of unfaulted authigenic clays, and not just clay volume, exert a significant control on the magnitude of permeability. However, fault‐related studies have neither characterized deformed authigenic clays nor addressed their influence on fluid‐flow. In this study laboratory permeabilities of faulted, authigenic clay bearing sandstones sampled from the Otway basin (Australia) and the Orcadian basin (UK) present trends which; (a) do not correspond to expected patterns of fluid‐flow in faulted clay‐bearing sandstones and, (b) cannot be explained using published models of permeability related to changing clay volume. Microscopic analysis shows that faulting has disaggregated authigenic clays and, similarly to framework grain deformation, comminuted and sheared clay grains. However, instead of impeding fluid‐flow, analysis of pore networks (using mercury injection porosimetry) showed that faulting of authigenic clays has increased pore connectivity, contributing to increased magnitude of permeability and development of permeability anisotropy. Contrary to published results of faulting and fluid‐flow in impure sandstones, our results show that fault related processes involving the formation of clays in the fault zone can increase permeability and reduce the capillary threshold pressures of fault rocks relative to the unfaulted host rock.
    • Post-irradiation surface viscoelastic integrity of photo-polymerized resin-based composites.

      Algamaiah, Hamad; email: dr.algamaiah@gmail.com; Watts, David C; email: david.watts@manchester.ac.uk (2021-09-27)
      A class of ultra-rapid-cure resin-based composites (RBCs) exhibited immediate post-irradiation surface viscoelastic integrity using an indentation-creep/recovery procedure. The aim of this study was to determine whether such behavior is more generally characteristic of a wider range of RBCs. Eight representative RBCs were selected based on different clinical categories: three bulkfills (OBF, Filtek One Bulk Fill; VBF, Venus Bulkfill; EBF, Estelite Bulkfill), three conventional non-flowables (XTE, Filtek Supreme XTE; GSO, GrandioSo; HRZ, Harmonize) and conventional flowables (XTF, Filtek Supreme XTE Flow; GSF, GrandioSo Flow). Stainless steel split molds were used to fabricate cylindrical specimens (4mm (dia)×4mm). These were irradiated (1.2W/cm ) for 20s on the top surface. Post-irradiation specimens (n=3), within their molds, were centrally loaded with a flat-ended 1.5mm diameter indenter under 14MPa stress: either immediately (<2min) or after 24h delayed indentation. Stress was maintained for 2h, then - after removal - recovery measurements continued for a further 2h. Indentation depth (%) versus time was measured continuously to an accuracy of <0.1μm. Data were analyzed by One-way ANOVA and Tukey post-hoc tests (α=0.05). Time-dependent viscoelastic indentation was observed for all RBCs. For immediate indentation, the maximum indentation range was 1.43-4.92%, versus 0.70-2.22% for 24h delayed indentation. Following 2h recovery, the residual indentation range was 0.86-3.58% after immediate indentation, reducing to 0.22-1.27% for delayed indentation. The greatest immediate indentation was shown by VBF followed by XTF and GSF. OBF, HRZ, XTE and GSO had significantly lower indentations (greater hardness). XTE showed a significantly reduced indentation maximum compared to OBF (p<0.05). Indentations delayed until 24h post-irradiation were reduced (p<0.05) for most materials. The indentation-creep methodology effectively characterized resin-based composites within several categories. Viscoelastic properties evaluated by the indentation-creep method confirmed that highly filled RBCs were more resistant to indentation. Indentations were reduced after 24h post-irradiation due to further matrix-network development. [Abstract copyright: Copyright © 2021. Published by Elsevier Inc.]
    • Influence of curing modes on thermal stability, hardness development and network integrity of dual-cure resin cements.

      Aldhafyan, Mohammed; Silikas, Nikolaos; email: nick.silikas@manchester.ac.uk; Watts, David C; email: david.watts@manchester.ac.uk (2021-09-27)
      To explore the effect of different curing modes of conventional and self-adhesive dual-cure resin cements on their rates of thermal decomposition, hardness development and network integrity. Five self-adhesive (PANAVIA SA, RelyX Universal Resin, RelyX Unicem 2, Bifix SE and SpeedCEM Plus) and three conventional (PANAVIA V5, Nexus Third Generation and RelyX Ultimate Universal) dual-cure resin cements were investigated. Thermal decomposition stages, initial onset temperatures, the maximum rate of mass-loss and the filler mass-fraction of each resin cement were analysed by thermogravimetric analysis (TGA). Surface hardness was measured at 1h post-cure and after 24h of dry storage at 37°C. The relative network integrities were estimated from reductions in hardness after 168h of water storage. Data were analysed via one-way ANOVA, Tukey post-hoc tests and paired/independent sample t-tests (a=0.05). No difference was apparent between TGA data for self-cured and light-cured specimens. Numerical differentiation of mass-loss versus temperature showed either single or multiple peaks. For the set of 8 cements, the maximum rate of mass-loss (%/°C) correlated negatively with residual mass at 600°C. All dry-stored cements increased in hardness from 1 to 24h, ranging from 20.4% to 52.6% for light-cure mode and from 41.3% to 112.6% for self-cure. After 168h water storage, the hardness of cements decreased: by 18.5%-36.2% for light-cured and by 9.8%-17.9% for self-cured. Overall, surface hardness was greater for light-cured cements. The initial onset temperature (IOT) of thermal decomposition correlated negatively with the hardness decrease produced by water-storage: r =0.77 for light-cure and r =0.88 for self-cure. This provided the basis for a relative scale of composite network integrity, probably reflecting differences in cross-link density. Light-curing, where possible, remains beneficial to the hardness and related properties of dual-cure resin cements. Combination of TG analysis and solvent softening experiments give an indication of relative network integrity - between materials - and their relative cross-link densities. [Abstract copyright: Copyright © 2021. Published by Elsevier Inc.]
    • The impact of COVID-19 lockdowns on the genetic integrity of your mouse colonies.

      Moncaut, Natalia; email: natalia.moncaut@cruk.manchester.ac.uk; Hart-Johnson, Sarah; email: sarah.hart-johnson@crick.ac.uk (2021-09-30)
    • Impact of hypoxia on cervical cancer outcomes.

      Datta, Anubhav; orcid: 0000-0002-5234-2315; email: anubhav.datta@manchester.ac.uk; West, Catharine; O'Connor, James P B; Choudhury, Ananya; Hoskin, Peter (2021-09-30)
      The annual global incidence of cervical cancer is approximately 604 000 cases/342 000 deaths, making it the fourth most common cancer in women. Cervical cancer is a major healthcare problem in low and middle income countries where 85% of new cases and deaths occur. Secondary prevention measures have reduced incidence and mortality in developed countries over the past 30 years, but cervical cancer remains a major cause of cancer deaths in women. For women who present with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO 2018) stages IB3 or upwards, chemoradiation is the established treatment. Despite high rates of local control, overall survival is less than 50%, largely due to distant relapse. Reducing the health burden of cervical cancer requires greater individualization of treatment, identifying those at risk of relapse and progression for modified or intensified treatment. Hypoxia is a well known feature of solid tumors and an established therapeutic target. Low tumorous oxygenation increases the risk of local invasion, metastasis and treatment failure. While meta-analyses show benefit, many individual trials targeting hypoxia failed in part due to not selecting patients most likely to benefit. This review summarizes the available hypoxia-targeted strategies and identifies further research and new treatment paradigms needed to improve patient outcomes. The applications and limitations of hypoxia biomarkers for treatment selection and response monitoring are discussed. Finally, areas of greatest unmet clinical need are identified to measure and target hypoxia and therefore improve cervical cancer outcomes. [Abstract copyright: © IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Genetic and process engineering strategies for enhanced recombinant N -glycoprotein production in bacteria

      Pratama, Fenryco; Linton, Dennis; Dixon, Neil; orcid: 0000-0001-9065-6764; email: neil.dixon@manchester.ac.uk (BioMed Central, 2021-10-14)
      Abstract: Background: The production of N-linked glycoproteins in genetically amenable bacterial hosts offers great potential for reduced cost, faster/simpler bioprocesses, greater customisation, and utility for distributed manufacturing of glycoconjugate vaccines and glycoprotein therapeutics. Efforts to optimize production hosts have included heterologous expression of glycosylation enzymes, metabolic engineering, use of alternative secretion pathways, and attenuation of gene expression. However, a major bottleneck to enhance glycosylation efficiency, which limits the utility of the other improvements, is the impact of target protein sequon accessibility during glycosylation. Results: Here, we explore a series of genetic and process engineering strategies to increase recombinant N-linked glycosylation, mediated by the Campylobacter-derived PglB oligosaccharyltransferase in Escherichia coli. Strategies include increasing membrane residency time of the target protein by modifying the cleavage site of its secretion signal, and modulating protein folding in the periplasm by use of oxygen limitation or strains with compromised oxidoreductase or disulphide-bond isomerase activity. These approaches achieve up to twofold improvement in glycosylation efficiency. Furthermore, we also demonstrate that supplementation with the chemical oxidant cystine enhances the titre of glycoprotein in an oxidoreductase knockout strain by improving total protein production and cell fitness, while at the same time maintaining higher levels of glycosylation efficiency. Conclusions: In this study, we demonstrate that improved protein glycosylation in the heterologous host could be achieved by mimicking the coordination between protein translocation, folding and glycosylation observed in native host such as Campylobacter jejuni and mammalian cells. Furthermore, it provides insight into strain engineering and bioprocess strategies, to improve glycoprotein yield and titre, and to avoid physiological burden of unfolded protein stress upon cell growth. The process and genetic strategies identified herein will inform further optimisation and scale-up of heterologous recombinant N-glycoprotein production.
    • Selection of endogenous control genes for normalising gene expression data derived from formalin-fixed paraffin-embedded tumour tissue

      Smith, Tim A. D.; email: tim.smith@manchester.ac.uk; AbdelKarem, Omneya A.; Irlam-Jones, Joely J.; Lane, Brian; Valentine, Helen; Bibby, Becky A. S.; Denley, Helen; Choudhury, Ananya; West, Catharine M. L. (Nature Publishing Group UK, 2020-10-14)
      Abstract: Quantitative real time polymerase chain reaction (qPCR) data are normalised using endogenous control genes. We aimed to: (1) demonstrate a pathway to identify endogenous control genes for qPCR analysis of formalin-fixed paraffin-embedded (FFPE) tissue using bladder cancer as an exemplar; and (2) examine the influence of probe length and sample age on PCR amplification and co-expression of candidate genes on apparent expression stability. RNA was extracted from prospective and retrospective samples and subject to qPCR using TaqMan human endogenous control arrays or single tube assays. Gene stability ranking was assessed using coefficient of variation (CoV), GeNorm and NormFinder. Co-expressed genes were identified from The Cancer Genome Atlas (TCGA) using the on-line gene regression analysis tool GRACE. Cycle threshold (Ct) values were lower for prospective (19.49 ± 2.53) vs retrospective (23.8 ± 3.32) tissues (p < 0.001) and shorter vs longer probes. Co-expressed genes ranked as the most stable genes in the TCGA cohort by GeNorm when analysed together but ranked lower when analysed individually omitting co-expressed genes indicating bias. Stability values were < 1.5 for the 20 candidate genes in the prospective cohort. As they consistently ranked in the top ten by CoV, GeNorm and Normfinder, UBC, RPLP0, HMBS, GUSB, and TBP are the most suitable endogenous control genes for bladder cancer qPCR.
    • Understanding the structural diversity of chitins as a versatile biomaterial

      Hou, Jiaxin; Aydemir, Berk Emre; Dumanli, Ahu Gümrah; orcid: 0000-0002-7106-4875; email: ahugumrah.parry@manchester.ac.uk (The Royal Society Publishing, 2021-08-02)
      Chitin is one of the most abundant biopolymers, and it has adopted many different structural conformations using a combination of different natural processes like biopolymerization, crystallization and non-equilibrium self-assembly. This leads to a number of striking physical effects like complex light scattering and polarization as well as unique mechanical properties. In doing so, chitin uses a fine balance between the highly ordered chain conformations in the nanofibrils and random disordered structures. In this opinion piece, we discuss the structural hierarchy of chitin, its crystalline states and the natural biosynthesis processes to create such specific structures and diversity. Among the examples we explored, the unified question arises from the generation of completely different bioarchitectures like the Christmas tree-like nanostructures, gyroids or helicoidal geometries using similar dynamic non-equilibrium growth processes. Understanding the in vivo development of such structures from gene expressions, enzymatic activities as well as the chemical matrix employed in different stages of the biosynthesis will allow us to shift the material design paradigms. Certainly, the complexity of the biology requires a collaborative and multi-disciplinary research effort. For the future's advanced technologies, using chitin will ultimately drive many innovations and alternatives using biomimicry in materials science. This article is part of the theme issue ‘Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 1)'.
    • Iron Is Filtered by the Kidney and Is Reabsorbed by the Proximal Tubule

      Wareing, Mark; Smith, Craig P.; email: craig.smith@manchester.ac.uk (Frontiers Media S.A., 2021-09-30)
      The aim of this study was to determine the iron (Fe) concentration profile within the lumen of the S2 renal proximal convoluted tubule (PCT) and to resolve whether this nephron segment transported Fe. To do this, we performed in vivo renal micropuncture on Wistar rats, collected PCT tubular fluid from superficial nephrons, and measured Fe concentration. The Fe concentration profile along the S2 PCT suggested significant Fe reabsorption. Proximal tubules were also microperfused in vivo with physiological solutions containing Fe and Zn, Cu, Mn, or Cd. PCTs perfused with 12μmol.l−1 55FeCl3 reabsorbed 105.2±12.7 fmol.mm−1.min−1 Fe, 435±52pmol.mm-1.min−1 Na, and 2.7±0.2nl.mm−1.min−1 water (mean ± SEM; n=19). Addition of ascorbate (1mmol.l−1) to the perfusate did not significantly alter Fe, Na, or water reabsorption. Supplementing the control perfusate with 60μmol.l−1 FeSO4 significantly decreased 55Fe uptake. Recalculating for the altered molar activity following addition of unlabeled Fe revealed a three-fold increase in Fe flux. Addition to the perfusate 12μmol.l−1 CuSO4, MnSO4, CdSO4, or ZnSO4 did not affect Fe, Na, or water flux. In conclusion, (1) in vivo, S2 PCTs of rat reabsorb Fe and (2) Fe is reabsorbed along the PCT via a pathway that is insensitive to Cu, Mn, Cd, or Zn. Together, these data demonstrate for the first time the hitherto speculated process of renal Fe filtration and subsequent tubular Fe reabsorption in a living mammal.
    • The Relationship between the Therapeutic Alliance and Suicidal Experiences in People with Psychosis Receiving Therapy

      Huggett, Charlotte; orcid: 0000-0002-7566-6224; email: charlotte.huggett@postgrad.manchester.ac.uk; Gooding, Patricia; email: Patricia.A.Gooding@manchester.ac.uk; Haddock, Gillian; email: gillian.haddock@manchester.ac.uk; Pratt, Daniel; orcid: 0000-0001-8843-1224; email: daniel.pratt@manchester.ac.uk (MDPI, 2021-10-12)
      Few studies have examined the relationship between the therapeutic alliance in therapy and suicidal experiences. No studies have examined this relationship with people with non-affective psychosis. The present study sought to redress this gap in the literature. Sixty-four participants with non-affective psychosis and suicidal experiences who were receiving a suicide-focused cognitive therapy were recruited. Self-reported suicidal ideation, suicide plans, suicide attempts, depression, and hopelessness were collected from participants prior to starting therapy. Suicidal experience measures were collected again post-therapy at 6 months. Therapeutic alliance ratings were completed by clients and therapists at session 4 of therapy. Dose of therapy was documented in number of minutes of therapy. Data were analyzed using correlation coefficients, independent samples t-tests, a multiple hierarchical regression, and a moderated linear regression. There was no significant relationship found between suicidal ideation prior to therapy and the therapeutic alliance at session 4, rated by both client and therapist. However, there was a significant negative relationship between the client-rated therapeutic alliance at session 4 and suicidal ideation at 6 months, after controlling for pre-therapy suicidal ideation, depression, and hopelessness. Furthermore, the negative relationship between the client-rated alliance and suicidal ideation was the strongest when number of minutes of therapy was 15 h or below. A stronger therapeutic alliance developed in the first few sessions of therapy is important in ameliorating suicidal thoughts in people with psychosis. Nevertheless, it is not necessarily the case that more hours in therapy equates to a cumulative decrease in suicidal ideation of which therapists could be mindful. A limitation of the current study was that the alliance was analyzed only at session 4 of therapy, which future studies could seek to redress.
    • Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study.

      Valle, Juan W; email: juan.valle@manchester.ac.uk; Vogel, Arndt; Denlinger, Crystal S; He, Aiwu Ruth; Bai, Li-Yuan; Orlova, Rashida; Van Cutsem, Eric; Adeva, Jorge; Chen, Li-Tzong; Obermannova, Radka; et al. (2021-10)
      Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin-gemcitabine in patients with locally advanced or metastatic biliary tract cancer. We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m and gemcitabine 1000 mg/m (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing. Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1-14·1). Median progression-free survival was 6·5 months (80% CI 5·7-7·1) in the ramucirumab group, 7·0 months (6·2-7·1) in the merestinib group, and 6·6 months (5·6-6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90-1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73-1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]). Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection. Eli Lilly and Company. [Abstract copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.]
    • Nitric oxide mediates activity-dependent change to synaptic excitation during a critical period in Drosophila

      Giachello, Carlo N. G.; Fan, Yuen Ngan; Landgraf, Matthias; Baines, Richard A.; email: Richard.Baines@manchester.ac.uk (Nature Publishing Group UK, 2021-10-13)
      Abstract: The emergence of coordinated network function during nervous system development is often associated with critical periods. These phases are sensitive to activity perturbations during, but not outside, of the critical period, that can lead to permanently altered network function for reasons that are not well understood. In particular, the mechanisms that transduce neuronal activity to regulating changes in neuronal physiology or structure are not known. Here, we take advantage of a recently identified invertebrate model for studying critical periods, the Drosophila larval locomotor system. Manipulation of neuronal activity during this critical period is sufficient to increase synaptic excitation and to permanently leave the locomotor network prone to induced seizures. Using genetics and pharmacological manipulations, we identify nitric oxide (NO)-signaling as a key mediator of activity. Transiently increasing or decreasing NO-signaling during the critical period mimics the effects of activity manipulations, causing the same lasting changes in synaptic transmission and susceptibility to seizure induction. Moreover, the effects of increased activity on the developing network are suppressed by concomitant reduction in NO-signaling and enhanced by additional NO-signaling. These data identify NO signaling as a downstream effector, providing new mechanistic insight into how activity during a critical period tunes a developing network.
    • Investigating top tagging with Y m -Splitter and N-subjettiness

      Dasgupta, Mrinal; Helliwell, Jack; orcid: 0000-0002-8725-7794; email: jack.helliwell@manchester.ac.uk (Springer Berlin Heidelberg, 2021-10-12)
      Abstract: We study top-tagging from an analytical QCD perspective focussing on the role of two key steps therein: a step to find three-pronged substructure and a step that places constraints on radiation. For the former we use a recently introduced modification of Y-Splitter, known as Ym-Splitter, and for the latter we use the well-known N-subjettiness variable. We derive resummed results for this combination of variables for both signal jets and background jets, also including pre-grooming of the jet. Our results give new insight into the performance of top tagging tools in particular with regard to the role of the distinct steps involved.