• Nanometre imaging of Fe 3 GeTe 2 ferromagnetic domain walls

      Hopkinson, David G; orcid: 0000-0003-4259-7450; Seki, Takehito; Clark, Nicholas; Chen, Runze; Zou, Yichao; Kimura, Ayumi; Gorbachev, Roman V; Thomson, Thomas; Shibata, Naoya; Haigh, Sarah J; orcid: 0000-0001-5509-6706; email: sarah.haigh@manchester.ac.uk (IOP Publishing, 2021-02-23)
      Abstract: Fe3GeTe2 is a layered crystal which has recently been shown to maintain its itinerant ferromagnetic properties even when atomically thin. Here, differential phase contrast scanning transmission electron microscopy is used to investigate the domain structure in a Fe3GeTe2 cross-sectional lamella at temperatures ranging from 95 to 250 K and at nanometre spatial resolution. Below the experimentally determined Curie temperature (T C) of 191 K, stripe domains magnetised along 〈0001〉, bounded with 180◦ Bloch type domain walls, are observed, transitioning to mixed Bloch−Néel type where the cross-sectional thickness is reduced below 50 nm. When warming towards T C, these domains undergo slight restructuring towards uniform size, before abruptly fading at T C. Localised loss of ferromagnetic order is seen over time, hypothesised to be a frustration of ferromagnetic order from ambient oxidation and basal cracking, which could enable selective modification of the magnetic properties for device applications.
    • Nanometre imaging of Fe 3 GeTe 2 ferromagnetic domain walls

      Hopkinson, David G; orcid: 0000-0003-4259-7450; Seki, Takehito; Clark, Nicholas; Chen, Runze; Zou, Yichao; Kimura, Ayumi; Gorbachev, Roman V; Thomson, Thomas; Shibata, Naoya; Haigh, Sarah J; orcid: 0000-0001-5509-6706; email: sarah.haigh@manchester.ac.uk (IOP Publishing, 2021-02-23)
      Abstract: Fe3GeTe2 is a layered crystal which has recently been shown to maintain its itinerant ferromagnetic properties even when atomically thin. Here, differential phase contrast scanning transmission electron microscopy is used to investigate the domain structure in a Fe3GeTe2 cross-sectional lamella at temperatures ranging from 95 to 250 K and at nanometre spatial resolution. Below the experimentally determined Curie temperature (T C) of 191 K, stripe domains magnetised along 〈0001〉, bounded with 180◦ Bloch type domain walls, are observed, transitioning to mixed Bloch−Néel type where the cross-sectional thickness is reduced below 50 nm. When warming towards T C, these domains undergo slight restructuring towards uniform size, before abruptly fading at T C. Localised loss of ferromagnetic order is seen over time, hypothesised to be a frustration of ferromagnetic order from ambient oxidation and basal cracking, which could enable selective modification of the magnetic properties for device applications.
    • National Health Service interventions in England to improve care to Armed Forces veterans

      Bacon, Andrew; Martin, E; Swarbrick, R; Treadgold, A (BMJ Publishing Group, 2021-03-19)
      Armed Forces veterans (AFVs) are first and foremost citizens of the UK and are therefore—like all UK residents—entitled to universal healthcare, free at the point of need. This means that AFVs have nearly all their healthcare needs met by the NHS, which provides access to a full range of generic services. However, since 2013 there has been an Armed Forces team that can also support veterans. This review is an assessment of the work of this group over the last eight years. The health needs of AFVs have been investigated and are not significantly different from those of their demographically matched peers. However, due to their demographics, selection at recruitment and their roles, AFVs compared with the general population are more likely to be male, white and old and have fewer pre-existing or hereditary conditions. However, they do suffer from higher rates of musculoskeletal injury, different patterns of mental health illness and have historically been higher users—and abusers—of alcohol and tobacco. In addition to supporting mainstream services used by AFVs, the NHS in England commissions a bespoke range-specific ‘Priority’ NHS services such as those for mental health or for rehabilitation of veterans using prostheses. New interventions are continuing to be developed to improve AFVs’ healthcare and are aligned to the NHS Long Term Plan and the restoration and recovery plans after the COVID-19 pandemic.
    • National Health Service interventions in England to improve care to Armed Forces veterans.

      Bacon, Andrew; email: andy.bacon@nhs.net; Martin, E; Swarbrick, R; Treadgold, A (2021-03-19)
      Armed Forces veterans (AFVs) are first and foremost citizens of the UK and are therefore-like all UK residents-entitled to universal healthcare, free at the point of need. This means that AFVs have nearly all their healthcare needs met by the NHS, which provides access to a full range of generic services. However, since 2013 there has been an Armed Forces team that can also support veterans. This review is an assessment of the work of this group over the last eight years. The health needs of AFVs have been investigated and are not significantly different from those of their demographically matched peers. However, due to their demographics, selection at recruitment and their roles, AFVs compared with the general population are more likely to be male, white and old and have fewer pre-existing or hereditary conditions. However, they do suffer from higher rates of musculoskeletal injury, different patterns of mental health illness and have historically been higher users-and abusers-of alcohol and tobacco. In addition to supporting mainstream services used by AFVs, the NHS in England commissions a bespoke range-specific NHS services such as those for mental health or for rehabilitation of veterans using prostheses. New interventions are continuing to be developed to improve AFVs' healthcare and are aligned to the NHS Long Term Plan and the restoration and recovery plans after the COVID-19 pandemic. [Abstract copyright: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca 2+ -dependent mechanism

      Law, Betty Yuen Kwan; Michelangeli, Francesco; Qu, Yuan Qing; orcid: 0000-0003-3733-3661; Xu, Su-Wei; Han, Yu; Mok, Simon Wing Fai; Dias, Ivo Ricardo De Seabra Rodrigues; Javed, Masood-Ul-Hassan; Chan, Wai-Kit; Xue, Wei-Wei; et al. (Nature Publishing Group UK, 2019-12-27)
      Abstract: Resistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.
    • Negotiating Journalism: Core Values and Cultural Diversities

      Mbaya, Nancy, B. (SAGE Publications, 2019-06-17)
    • Neoadjuvant therapy or upfront surgery in advanced endometrial cancer: a systematic review protocol.

      McCarthy, Amy; Balfour, Katharine; El Sayed, Iman; Edmondson, Richard; Wan, Yee-Loi Louise; orcid: 0000-0003-1441-6050; email: louise.wan@manchester.ac.uk (2021-11-11)
      There is no consensus on the optimal treatment strategy for people with advanced endometrial cancer. Neoadjuvant therapies such as chemotherapy and radiotherapy have been employed to try to reduce the morbidity of surgery, improve its feasibility and/or improve functional performance in people considered unfit for primary surgery. The objective of this review is to assess whether neoadjuvant chemotherapy or radiotherapy improves health outcomes in people with advanced endometrial cancer when compared with upfront surgery. This review will consider both randomised and non-randomised studies that compare health outcomes associated with the neoadjuvant therapy and upfront surgery in advanced endometrial cancer. Potential studies for inclusion will be collated from electronic searches of OVID Medline, Embase, international trial registries and conference abstract lists. Data collection and extraction will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodological quality of the studies will be assessed using the Risk of Bias 2 and Risk of Bias in Non-randomised Studies of Interventions tools. If appropriate, we will perform a meta-analysis and provide summary statistics for each outcome. Ethics approval was not required for this study. Once complete, we will publish our findings in peer-reviewed publications, via conference presentations and to update relevant practice guidelines. [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Network organisation and the dynamics of tubules in the endoplasmic reticulum

      Perkins, Hannah T.; Allan, Victoria J.; email: viki.allan@manchester.ac.uk; Waigh, Thomas A.; email: t.a.waigh@manchester.ac.uk (Nature Publishing Group UK, 2021-08-10)
      Abstract: The endoplasmic reticulum (ER) is a eukaryotic subcellular organelle composed of tubules and sheet-like areas of membrane connected at junctions. The tubule network is highly dynamic and undergoes rapid and continual rearrangement. There are currently few tools to evaluate network organisation and dynamics. We quantified ER network organisation in Vero and MRC5 cells, and developed an analysis workflow for dynamics of established tubules in live cells. The persistence length, tubule length, junction coordination number and angles of the network were quantified. Hallmarks of imbalances in ER tension, indications of interactions with microtubules and other subcellular organelles, and active dynamics were observed. Clear differences in dynamic behaviour were observed for established tubules at different positions within the cell using itemset mining. We found that tubules with activity-driven fluctuations were more likely to be located away from the cell periphery and a population of peripheral tubules with no signs of active motion was found.
    • Neurodiverse transactional development may confound primary attachment inferences ‐ Commentary on Martin et al 2020. https://doi.org/10.1111/desc.12953

      Green, Jonathan; orcid: 0000-0002-0143-181X; email: jonathan.green@manchester.ac.uk; Wan, Ming Wai (2021-07-08)
    • Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis

      Conen, Silke; orcid: 0000-0002-2885-4409; email: silke.conen@manchester.ac.uk; Gregory, Catherine J.; Hinz, Rainer; orcid: 0000-0002-7808-9207; Smallman, Richard; Corsi-Zuelli, Fabiana; orcid: 0000-0001-9202-3987; Deakin, Bill; orcid: 0000-0002-2750-962X; Talbot, Peter S.; orcid: 0000-0003-3492-0801 (Nature Publishing Group UK, 2020-06-30)
      Abstract: Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), which is upregulated in activated microglia, is a method for investigating whether immune activation is evident in the brain of adults with schizophrenia. This study aimed to measure TSPO availability in the largest patient group to date, and to compare it between patients with recent onset (ROS) and established (ES) schizophrenia. In total, 20 ROS patients (14 male), 21 ES (13 male), and 21 healthy controls completed the study. Patients were predominantly antipsychotic-medicated. Participants underwent a PET scan using the TSPO-specific radioligand [11C](R)-PK11195. The primary outcome was binding potential (BPND) in the anterior cingulate cortex (ACC). Secondary outcomes were BPND in six other regions. Correlations were investigated between TSPO availability and symptom severity. Data showed that mean BPND was higher in older (ES and controls) compared with younger (ROS and controls) individuals, but did not significantly differ between ROS or ES and their respective age-matched controls (ACC; ANOVA main effect of diagnosis: F1,58 = 0.407, p = 0.526). Compared with controls, BPND was lower in antipsychotic-free (n = 6), but not in medicated, ROS patients. BPND in the ES group was negatively correlated with positive symptoms, and positively correlated with negative symptom score. Our data suggest ageing is associated with higher TSPO but a diagnosis of schizophrenia is not. Rather, subnormal TSPO levels in drug-free recent-onset patients may imply impaired microglial development and/or function, which is counteracted by antipsychotic treatment. The development of novel radioligands for specific immune-mechanisms is needed for further clarification.
    • Neutrally charged self-assembling peptide hydrogel recapitulates in vitro mechanisms of breast cancer progression.

      Clough, Helen C; email: helen.clough@manchester.ac.uk; O'Brien, Marie; email: marie.obrien@manchester.ac.uk; Zhu, Xinyi; email: xinyi.zhu@manchester.ac.uk; Miller, Aline F; email: a.miller@manchesterbiogel.com; Saiani, Alberto; email: a.saiani@manchester.ac.uk; Tsigkou, Olga; email: olga.tsigkou@manchester.ac.uk (2021-05-21)
      Self-assembling peptide hydrogels (SAPH) are a popular biomaterial due to their biocompatibility with a wide range of cell types, synthetic design, structural properties that provide a more accurate 3D microenvironment, and potential for cell- and/or drug-delivery system. Mimicking solid tumors in vitro using hydrogels is one method of testing anti-cancer drug efficacy and observing cancerous cell-ECM interactions within a 3D system. In this study, a SAPH, PeptiGel®Alpha1, was used to model in vitro the 3D breast tumor microenvironment. PeptiGel®Alpha1 is composed of entangled nanofibers with consistent diameter and mechanical properties similar to breast cancer that more accurately mimic the stiffness of breast tumor tissue than Matrigel® or collagen type I. PeptiGel®Alpha1 supported the viability and growth of the breast cancer cell lines MCF-7 and MDA-MB-231 and recapitulated key features of solid tumors such as hypoxia and invasion. MCF-7 cells in the hydrogels formed large spheroids resembling acini, while MDA-MB-231 remained dispersed. When treated with tamoxifen, PeptiGel®Alpha1 acted as a barrier, providing drug penetration geometry similar to that in vivo, providing better prediction of the drug effect. Finally, it was observed that MCF-7 cells engulfed the peptide matrix after 14 days, highlighting a potential use in drug delivery. PeptiGel®Alpha1 is a suitable platform for in vitro modeling of breast cancer. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
    • Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency

      Goenka, Anu; orcid: 0000-0002-8152-2155; Doherty, John A.; Al‐Farsi, Tariq; Jagger, Christopher; Banka, Siddharth; Cheesman, Edmund; Fagbemi, Andrew; Hughes, Stephen M.; Wynn, Robert F.; Hussell, Tracy; et al. (2020-09-15)
      Abstract: The glucose‐6‐phosphatase catalytic subunit 3 (G6PC3) encodes a ubiquitously expressed enzyme that regulates cytoplasmic glucose availability. Loss‐of‐function biallelic G6PC3 mutations cause severe congenital neutropenia and a diverse spectrum of extra‐hematological manifestations, among which inflammatory bowel disease (IBD) has been anecdotally reported. Neutrophil function and clinical response to granulocyte colony‐stimulating factor (G‐CSF) and hematopoietic stem cell transplantation (HSCT) were investigated in 4 children with G6PC3 deficiency‐associated IBD. G6PC3 deficiency was associated with early‐onset IBD refractory to treatment with steroids and infliximab. The symptoms of IBD progressed despite G‐CSF treatment. In vitro studies on the patients’ blood showed that neutrophils displayed higher levels of activation markers (CD11b, CD66b, and CD14), excessive IL‐8 and reactive oxygen species, and increased apoptosis and secondary necrosis. Secondary necrosis was exaggerated after stimulation with Escherichia coli and could be partially rescued with supplemental exogenous glucose. HSCT led to normalization of neutrophil function and remission of gastrointestinal symptoms. We conclude that neutrophils in G6PC3 deficiency release pro‐inflammatory mediators when exposed to gut bacteria, associated with intestinal inflammation, despite treatment with G‐CSF. HSCT is an effective therapeutic option in patients with G6PC3 deficiency‐associated IBD refractory to immune suppressants.
    • New extremal binary self-dual codes from block circulant matrices and block quadratic residue circulant matrices

      Gildea, J.; Kaya, A.; Taylor, R.; orcid: 0000-0002-8563-2212; Tylyshchak, A.; orcid: 0000-0001-7828-3416; Yildiz, B.; orcid: 0000-0001-8106-3123 (Elsevier, 2021-08-20)
      In this paper, we construct self-dual codes from a construction that involves both block circulant matrices and block quadratic residue circulant matrices. We provide conditions when this construction can yield self-dual codes. We construct self-dual codes of various lengths over F 2 and F 2 + u F 2 . Using extensions, neighbours and sequences of neighbours, we construct many new self-dual codes. In particular, we construct one new self-dual code of length 66 and 51 new self-dual codes of length 68.
    • New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder.

      Faridi, Rabia; orcid: 0000-0001-7788-8755; Rea, Alessandro; orcid: 0000-0002-6204-846X; Fenollar-Ferrer, Cristina; orcid: 0000-0003-4953-8891; O'Keefe, Raymond T; orcid: 0000-0001-8764-1289; Gu, Shoujun; Munir, Zunaira; orcid: 0000-0003-3342-9658; Khan, Asma Ali; orcid: 0000-0002-0894-3439; Riazuddin, Sheikh; orcid: 0000-0001-6012-0192; Hoa, Michael; orcid: 0000-0001-7469-2909; Naz, Sadaf; orcid: 0000-0002-1912-0235; et al. (2021-08-02)
      Hearing loss and impaired fertility are common human disorders each with multiple genetic causes. Sometimes deafness and impaired fertility, which are the hallmarks of Perrault syndrome, co-occur in a person. Perrault syndrome is inherited as an autosomal recessive disorder characterized by bilateral mild to severe childhood sensorineural hearing loss with variable age of onset in both sexes and ovarian dysfunction in females who have a 46, XX karyotype. Since the initial clinical description of Perrault syndrome 70 years ago, the phenotype of some subjects may additionally involve developmental delay, intellectual deficit and other neurological disabilities, which can vary in severity in part dependent upon the genetic variants and the gene involved. Here, we review the molecular genetics and clinical phenotype of Perrault syndrome and focus on supporting evidence for the eight genes (CLPP, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, RMND1, TWNK) associated with Perrault syndrome. Variants of these eight genes only account for approximately half of the individuals with clinical features of Perrault syndrome where the molecular genetic base remains under investigation. Additional environmental etiologies and novel Perrault disease-associated genes remain to be identified to account for unresolved cases. We also report a new genetic variant of CLPP, computational structural insight about CLPP and single cell RNAseq data for eight reported Perrault syndrome genes suggesting a common cellular pathophysiology for this disorder. Some unanswered questions are raised to kindle future research about Perrault syndrome. [Abstract copyright: © 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.]
    • New singly and doubly even binary [72,36,12] self-dual codes from M 2(R)G - group matrix rings

      Korban, Adrian; orcid: 0000-0001-5206-6480; Şahinkaya, Serap; Ustun, Deniz; orcid: 0000-0002-5229-4018 (Elsevier, 2021-09-17)
      In this work, we present a number of generator matrices of the form [ I 2 n | τ 2 ( v ) ] , where I 2 n is the 2 n × 2 n identity matrix, v is an element in the group matrix ring M 2 ( R ) G and where R is a finite commutative Frobenius ring and G is a finite group of order 18. We employ these generator matrices and search for binary [ 72 , 36 , 12 ] self-dual codes directly over the finite field F 2 . As a result, we find 134 Type I and 1 Type II codes of this length, with parameters in their weight enumerators that were not known in the literature before. We tabulate all of our findings.
    • New Technique to Improve the Ductility of Steel Beam to Column Bolted Connections: A Numerical Investigation

      Shaheen, Mohamed A.; email: m.shaheen@lboro.ac.uk; Galal, Mohamed Ahmed; orcid: 0000-0003-4263-0361; email: mohamed1982dh@yahoo.com; Cunningham, Lee S.; orcid: 0000-0002-7686-7490; email: lee.scott.cunningham@manchester.ac.uk; Foster, Andrew S. J.; email: AWFR@cowi.com (MDPI, 2021-10-22)
      A novel method to improve the robustness of steel end plate connections is presented in this paper. Existing commonly adopted techniques alter the stiffness of the beam or the end plate to improve the connection’s robustness. In this study, the robustness is enhanced by improving the contribution of the bolts to the rotational capacity of connections; the higher the bolts’ elongation, the higher the rotational capacity that can be achieved. However, the brittleness of the bolt material, combined with its small length, results in negligible elongation. Alternatively, the load path between the end plate and the bolts can be interrupted with a ductile element to achieve the required elongation. This can be achieved by inserting a steel sleeve with a designated length, thickness, and wall curvature between the end plate and the washer. The proposed sleeve should be designed so that its ultimate capacity is less than the force in the bolt at failure; accordingly, the sleeve develops a severe bending deformation before the failure of any connection components. Using a validated finite element model, end plate connections with various parameters are numerically investigated to understand the performance of the sleeve device. The proposed system substantially enhances the rotational capacity of the connections, ranging between 1.37 and 2.46 times that of the standard connection. It is also concluded that the sleeved connections exhibit a consistent elastic response with the standard connections, indicating the proposed system is compatible with codified elastic design approaches without modification. Furthermore, for a specific connection, various ductile responses can be achieved without altering the connection capacity nor configuration.
    • Next steps in dermatology training: choosing to enter higher speciality training and the transition from trainee to consultant dermatologist

      Ashraf, I.; orcid: 0000-0002-7246-5451; Chowdhury, M. M. U.; Murphy, R.; Griffiths, T. W.; Esmail, A.; Young, H. S.; orcid: 0000-0003-1538-445X; email: helen.s.young@manchester.ac.uk (2021-01-17)
      Summary: Background: Junior doctors are required to make career decisions at an early stage in their postgraduate training. Trainees also feel inadequately prepared for the transition to consultant roles. Aim: To explore the key factors influencing the choice of dermatology as a postgraduate medical career and to identify the training needs required for transition from trainee to consultant. Methods: An online questionnaire was designed to identify (i) why trainees chose a postgraduate medical career in dermatology, and (ii) the training required for transition from trainee to consultant. Results: In total, 46 responses were received from trainees in their first to final years (ST3–6), of whom 89% had undertaken an undergraduate dermatology placement, with a median duration of 2 weeks. Dermatology was considered as a career during medical school by 61% of trainees, and 41% confirmed their decision to pursue a career in dermatology during foundation training. The most influential factors involved in speciality selection were first, enjoyment of the work, second, postgraduate experience and equal third, the variety of the speciality and the regularity of working hours (P < 0.05). Mentoring was pivotal to career decision‐making. Significant numbers of trainees expressed a need for training in medical leadership, such as running an outpatient clinic and supervising clinical multidisciplinary teams. Although larger numbers of trainees had training in management of dermatology services, such as service improvement (52%) and local governance/National Health Service structures (43%), significant numbers of trainees had no training in writing job plans (89%) or business plans (85%). Training was significantly deficient for personal management and self‐awareness. Conclusion: Our study highlights important considerations in career decision‐making for trainees. Training in medical leadership, management and self‐awareness could be enhanced to ensure that trainees feel adequately equipped for consultant roles.
    • 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.
    • No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

      Dominguez-Valentin, Mev; orcid: 0000-0001-7856-0057; email: Mev.Dominguez.Valentin@rr-research.no; Plazzer, John-Paul; orcid: 0000-0001-5114-4301; email: johnpaul.plazzer@gmail.com; Sampson, Julian R.; email: Sampson@cardiff.ac.uk; Engel, Christoph; orcid: 0000-0002-7247-282X; email: christoph.engel@imise.uni-leipzig.de; Aretz, Stefan; orcid: 0000-0002-5228-1890; email: stefan.aretz@uni-bonn.de; Jenkins, Mark A.; email: m.jenkins@unimelb.edu.au; Sunde, Lone; email: l.sunde@rn.dk; Bernstein, Inge; email: i.bernstein@rn.dk; Capella, Gabriel; orcid: 0000-0002-4669-7320; email: capella.gabriel@gmail.com; Balaguer, Francesc; orcid: 0000-0002-0206-0539; email: fprunes@clinic.cat; et al. (MDPI, 2021-06-28)
      Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
    • ‘No idea of time’: Parents report differences in autistic children’s behaviour relating to time in a mixed-methods study

      Poole, Daniel; orcid: 0000-0002-7399-2499; email: daniel.poole@manchester.ac.uk; Gowen, Emma; orcid: 0000-0003-4788-4280; Poliakoff, Ellen; Jones, Luke A (SAGE Publications, 2021-04-30)
      An emerging body of research suggests that temporal processing may be disrupted in autistic children, although little is known about behaviours relating to time in daily life. In the present study, 113 parents of autistic and 201 parents of neurotypical children (aged 7–12 years) completed the It’s About Time questionnaire and open-ended questions about their child’s behaviour relating to time. The questionnaire scores were lower in the autistic compared with the neurotypical group, suggesting that behaviours are affected. Three key themes were identified using thematic analysis: autistic children had problems with temporal knowledge, learning about concepts relating to time, such as how to use the clock and language around time. There were differences in prospection with autistic children having more difficulties with how they thought about the future and prepared themselves for upcoming events. The final theme, monotropism, described how autistic children viewed their time as precious so they could maximise engagement in their interests. The present study indicates that behaviours relating to time can have a considerable impact on the daily lives of autistic children and their families. Further work exploring the development of temporal cognition in autism would be valuable for targeting effective educational and clinical support. Lay abstract: Many everyday activities require us to organise our behaviours with respect to time. There is some evidence that autistic children have problems with how they perceive and understand time. However, little is currently known about this, or the ways in which behaviours related to time are impacted in daily life. In this study, 113 parents of autistic children and 201 parents of neurotypical children completed a questionnaire and open-ended questions about their child’s behaviour relating to time. Questionnaire scores were lower in the autistic group compared with neurotypicals, which suggests that behaviours relating to time are affected in autistic children. The open-ended responses further confirmed that the autistic children struggled with time and that this impacted on them and their family. Three key themes were identified. Theme 1: autistic children have problems with learning about concepts relating to time such as telling the time from a clock and using words to describe time (hours, minutes, etc.) appropriately. Theme 2: autistic children think about the future differently. Planning and working under time pressure were described as a problem. Theme 3: autistic children have strong interests which take up a lot of their attention and worrying about having sufficient time to pursue these interests causes anxiety. This research indicates that behaviours related to time can have a considerable impact on the lives of autistic children and that targeted support may be required.