Now showing items 940-959 of 1421

• #### Nanometre imaging of Fe 3 GeTe 2 ferromagnetic domain walls

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

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

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.

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

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.

• #### Network organisation and the dynamics of tubules in the endoplasmic reticulum

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.
• #### Neuropsychiatric symptoms following metal-on-metal implant failure with cobalt and chromium toxicity

Background: There were at least 31,171 metal-on-metal (MoM) hip implants in the UK between 2003 and 2011. Some of these were subject to failure and widescale recalls and revisions followed. Method This is a presentation of ten cases (mean age 60 years) where we evaluated neuropsychiatric morbidity following metal-on-metal hip implant failure and revision. Implants were ASR total hip replacement (acetabular implant, taper sleeve adaptor and unipolar femoral implants) performed between 2005 and 2009. This case series describes, for the first time, neuropsychiatric complications after revision where there has been cobalt and chromium toxicity. Results Pre-revision surgery, nine patients had toxic levels of chromium and cobalt (mean level chromium 338 nmol/l, mean cobalt 669.4 nmol/l). Depression assessment showed 9 of 9 respondents fulfilled the BDI criteria for depression and 3 of these were being treated. 7 of 9 patients showing short term memory deficit with mean mini mental state examination score of 24.2. The normal population mean MMSE for this group would be expected to be 28 with <25 indicating possible dementia. Conclusions We found neurocognitive and depressive deficits after cobalt and chromium metallosis following MoM implant failure. Larger studies of neurocognitive effects are indicated in this group. There may be implications for public health.
• #### Neutrally charged self-assembling peptide hydrogel recapitulates in vitro mechanisms of breast cancer progression.

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

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

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.

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

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

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.
• #### New type I binary $[72, 36, 12]$ self-dual codes from $M_6(\mathbb{F}_2)G$ - Group matrix rings by a hybrid search technique based on a neighbourhood-virus optimisation algorithm

&lt;p style='text-indent:20px;'&gt;In this paper, a new search technique based on a virus optimisation algorithm is proposed for calculating the neighbours of binary self-dual codes. The aim of this new technique is to calculate neighbours of self-dual codes without reducing the search field in the search process (this technique is known in the literature due to the computational time constraint) but still obtaining results in a reasonable time (significantly faster when compared to the standard linear computational search). We employ this new search algorithm to the well-known neighbour method and its extension, the &lt;inline-formula&gt;&lt;tex-math id="M1"&gt;\begin{document}$k^{th}$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt;-range neighbours, and search for binary &lt;inline-formula&gt;&lt;tex-math id="M2"&gt;\begin{document}$[72, 36, 12]$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; self-dual codes. In particular, we present six generator matrices of the form &lt;inline-formula&gt;&lt;tex-math id="M3"&gt;\begin{document}$[I_{36} \ | \ \tau_6(v)],$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; where &lt;inline-formula&gt;&lt;tex-math id="M4"&gt;\begin{document}$I_{36}$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; is the &lt;inline-formula&gt;&lt;tex-math id="M5"&gt;\begin{document}$36 \times 36$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; identity matrix, &lt;inline-formula&gt;&lt;tex-math id="M6"&gt;\begin{document}$v$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; is an element in the group matrix ring &lt;inline-formula&gt;&lt;tex-math id="M7"&gt;\begin{document}$M_6(\mathbb{F}_2)G$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; and &lt;inline-formula&gt;&lt;tex-math id="M8"&gt;\begin{document}$G$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; is a finite group of order 6, to which we employ the proposed algorithm and search for binary &lt;inline-formula&gt;&lt;tex-math id="M9"&gt;\begin{document}$[72, 36, 12]$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; self-dual codes directly over the finite field &lt;inline-formula&gt;&lt;tex-math id="M10"&gt;\begin{document}$\mathbb{F}_2$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt;. We construct 1471 new Type I binary &lt;inline-formula&gt;&lt;tex-math id="M11"&gt;\begin{document}$[72, 36, 12]$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; self-dual codes with the rare parameters &lt;inline-formula&gt;&lt;tex-math id="M12"&gt;\begin{document}$\gamma = 11, 13, 14, 15, 17, 19, 20, 21, 22, 23, 25, 26, 28, 29, 30, 31, 32$\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; in their weight enumerators.&lt;/p&gt;