WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a member of C2-WW-HECT E3 ligase family. Although it may execute carcinostatic actions in some scenarios, WWP1 functions as an oncoprotein under most circumstances. Here, we comprehensively review reports on regulation of WWP1 and its roles in tumorigenesis. We summarize the WWP1-mediated ubiquitinations of diverse proteins and the signaling pathways they involved, as well as the mechanisms how they affect cancer formation and progression. According to our analysis of database, in combination with previous reports, we come to a conclusion that WWP1 expression is augmented in various cancers. Gene amplification, as well as expression regulation mediated by molecules such as non-coding RNAs, may account for the increased mRNA level of WWP1. Regulation of enzymatic activity is another important facet to upregulate WWP1-mediated ubiquitinations. Based on the published data, we conclude that WWP1 employs interactions between multiple domains to autoinhibit its polyubiquitination activity in a steady state. Association of some substrates can partially release certain autoinhibition-related domains and make WWP1 have a moderate activity of polyubiquitination. Some cancer-related mutations can fully disrupt the inhibitory interactions and make WWP1 hyperactive. High expression level or hyperactivation of WWP1 may abnormally enhance polyubiquitinations of some oncoproteins or tumor suppressors, such as ΔNp63α, PTEN and p27, and ultimately promote cell proliferation, survival, migration and invasion in tumorigenesis. Given the dysregulation and oncogenic functions of WWP1 in some cancer types, it is promising to explore some therapeutic inhibitors to tune down its activity. WWP1 is highly expressed in multiple tissues (WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is also known as AIP5 (Atropin-1-interacting protein 5) or TIUL1 (TG-interacting ubiquitin ligase 1) . It belo tissues , where i tissues . Vast ev tissues .WWP1 gene is highly conserved from C. elegance to mammals  stimulates transcription of echanism . This suechanism . Tumor nechanism . Data frechanism . In combechanism , this inechanism . Data frechanism . Pier Paechanism . Besidesechanism , severalechanism , miR-21 echanism , miR-30aechanism , miR-129echanism , miR-142echanism , and miRechanism , inhibitechanism . All theWWP1 gene generates at least 6 isotypes of protein in homo sapiens (2+-dependent lipid-binding (C2) domain, four WW domains (WW1∼4) in the middle, and a homologous to the E6-AP carboxyl terminus (HECT) domain  in the HECT domain occupies the canonical PY motif-binding site of WW4; WW2 and WW3 stabilize both termini of 2,3-linker . Thus, WData from Yu-Ru Lee et al. indicate that the interaction between the 2,3-linker region and the HECT domain can be mediated by either homodimerization or intra-interaction, both of which lead to an autoinhibition of WWP1 E3 ligase activity. Two germline point mutations in the N-lobe, K740N and N745S, may hyperactivate the polyubiquitination activity of WWP1 .Generally speaking, the manner of interaction between an E3 ligase and a substrate is a major determinant of the ubiquitination type. EGFR pathway substrate clone 15 (EPS15) does not have a PY motif. It employs its ubiquitin binding motif 2 (UIM2) to recruit WWP1, which monoubiquitinates EPS15 . UIMs usBased on the reports mentioned above, we summarize the regulation of WWP1 activity as follows and depict it in WW domain-containing E3 ubiquitin protein ligase 1 can directly add monoubiquitin or different polyubiquitin chains to a variety of substrate proteins and consequently modulate their stability, trafficking, or functions . These WLike its homologues, Smad ubiquitination regulatory factors (SMURFs), WWP1 mediates polyubiquitination of several Smad proteins. WW domain-containing E3 ubiquitin protein ligase 1 can also regulate epidermal growth factor (EGF) signaling and its downstream pathways such as PI3K-AKT and Ras-ERK, which can promote cell proliferation and chemoresistance . OverexpPhosphatase and tensin homolog (PTEN) is a classical tumor suppressor that antagonizes PI3K-AKT signaling . In its WNT signaling pathways, including the canonical WNT pathway and the WNT-planar cell polarity (WNT-PCP) relay, modulate actin cytoskeleton organization to promote cellular motility . MacGurnp53 family transcription factors, including p53, p63, and p73 proteins, play crucial roles in kinds of cancers. Aaron Laine et al. reported that WWP1 directly binds to p53, though p53 does not have a PY motif. This physical interaction leads to modification of p53 with a monoubiquitin or an unidentified polyubiquitin chain, which intriguingly stabilizes p53 instead of targeting it for degradation. WWP1-mediated modifications also result in nuclear export of p53 and a concomitant decrease in its transcriptional activities . This isWW domain-containing E3 ubiquitin protein ligase 1 can also polyubiquitinate and destabilize Krüppel-like factors 2 and 5 (KLF2 and KLF5) . KLF5 isIn addition, WWP1 is involved in tumorigenesis via ubiquitinating other proteins and targeting them for proteasomal degradation. The cyclin/CDK protein kinase inhibitor, p27, can be ubiquitinated by WWP1 , resultiAs mentioned above, WWP1 is widely accepted as an oncoprotein and is upregulated in multiple cancer types due to gene amplification . Besidesin vitro experiment and found that K740N and N745S mutations do not affect E3 ligase activity, and both mutants show similar dependencies to those of wild-type WWP1 in terms of allosteric activation (in vitro catalytic reactions with purified WWP1 from E. Coli. These main cancer-related WWP1 mutations are listed in Numerous mutations have been reported in human cancers, which can cause dysregulation of WWP1 activity. tivation . This diOn the other hand, WWP1 is downregulated in several cancer types  and may To sum up, WWP1 is a cardinal E3 ligase, which mediates ubiquitination of a wide range of proteins. For the most part, WWP1-mediated modifications are K48 polyubiquitination, which promotes proteasomal degradation of substrate proteins. WWP1 also adds monoubiquitin or other types of polyubiquitin chains, which may affect trafficking, localization, lysosomal degradation, and enzymatic activity of the modified proteins. Though functioning as a tumor suppressor under some circumstances, WWP1 is generally accepted as an oncoprotein. Via a plethora of substrates, WWP1 regulates kaleidoscopic signaling pathways such as TGFβ, EGF, WNT, PI3K-AKT, and Hippo pathways, consequently promoting or inhibiting neoplasia and progression of diverse cancers . The conOwing to gene amplification and regulation by transcription factors such as MYC and p53 as well as a batch of non-coding RNAs , WWP1 isThe hyperactive state and oncogenic functions of WWP1 in some cancer types make it possible as a therapeutic target. A recent investigation performed by LK and YuJ wrote the manuscript. CL and YoJ revised and proofread the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The crystal structure of the ADAMTS13 tandem CUB1 and CUB2 domains reveals how protease global latency is conferred. ADAMTS13 is a plasma metalloprotease that is essential for the regulation of von Willebrand factor (VWF) function, mediator of platelet recruitment to sites of blood vessel damage. ADAMTS13 function is dynamically regulated by structural changes induced by VWF binding that convert it from a latent to active conformation. ADAMTS13 global latency is manifest by the interaction of its C-terminal CUB1-2 domains with its central Spacer domain. We resolved the crystal structure of the ADAMTS13 CUB1-2 domains revealing a previously unreported configuration for the tandem CUB domains. Docking simulations between the CUB1-2 domains with the Spacer domain in combination with enzyme kinetic functional characterization of ADAMTS13 CUB domain mutants enabled the mapping of the CUB1-2 domain site that binds the Spacer domain. Together, these data reveal the molecular basis of the ADAMTS13 Spacer-CUB interaction and the control of ADAMTS13 global latency. Von Willebrand factor (VWF) is produced by both endothelial cells and platelets and secreted upon stimulation as disulfide-linked multimers containing up to ~100 VWF units  that occlude the active-site cleft , it unfolds to facilitate platelet capture. The VWF A2 domain also unfolds to expose the ADAMTS13 cleavage site and exosite binding regions. ADAMTS13 first interacts with the VWF D4-CK region, which disrupts the Spacer-CUB domain–mediated “global latency”  that are essential for the Spacer-CUB interaction  at its N terminus to maltose-binding protein (MBP). This was expressed in S2 cells and enabled expression of uniformly monomeric and monodisperse MBP-CUB1-2. We isolated the 70-kDa MBP-CUB1-2 fusion protein through a combination of Ni2+-chelating chromatography and gel filtration. Purified MBP-ADAMTS13 CUB1-2 was crystallized with the structure determined to a resolution of 2.8 Å (The ADAMTS13 CUB1-2 domain expression construct spans residues Serof 2.8 Å . The ent1192-Cys1213) and CUB2 loops L10 with L11 (Cys1299-Cys1325) (1236-Cys1254) linking loops L5 and L7 is conserved between other CUB domains but missing in CUB2 . ThCys1325) . The sec1235 and Asn1354, respectively, in homologous positions on loops L5 and L13  and are both assumed to be flexible. CUB1 and CUB2 are connected by a short linker loop (Leu1290-Glu1298) with the domains aligning in opposing orientations related by a ~180° rotation of the jelly roll structure. CUB1 β sheet #1 and CUB2 β sheet #3 both present a concave shape packing against each other at an angle of approximately 90° creating an extended axial surface, while β sheet #2 and #4 form convex surfaces located radially  with each other than other tandem CUB domains. CUB1-2 also has additional interesting surface features, including two hydrophobic patches that are composed of Leu-Trp-Trp residues in a triangular arrangement . These hydrophobic patches are surrounded by charged surface residues—positively charged in CUB1 β sheet #1 (The tandem CUB1-2 structure we observe is novel. The CUB1-2 domains share a much larger interface (758 Åsheet #1  and negasheet #1 .On either side of the interdomain cleft are two pockets: (i) a deep pocket (P1) composed of residues from CUB1 β sheet #1 and CUB2 loops L12, L14, and L16, and (ii) a shallow pocket (P2) composed of side chains from the linker loop, CUB2 β sheet #3 and CUB1 loop L6 (CUB domains exhibit a characteristic β sandwich structure composed of ~110 amino acids and are often repeated in multidomain proteins (fig. S2)  (2+-binding CUB domains. All the available tandem CUB domain structures coordinate Ca2+ ions in a conserved manner. Ca2+ binding can be predicted in many other multi-CUB domain proteins due to the presence of the conserved Ca2+-binding motif (fig. S2)  . The root mean square deviation (RMSD) values for the seven most similar CUB structures range from 2.4 to 2.9 Å, with z scores in the range of 8.7 to 13.0 despite amino acid identities in the range of only 13 to 18%. A similar analysis using the CUB2 structure yielded the same top seven CUB domain hits and RMSD values of 2.4 to 2.9 Å, z scores in the range of 8.7 to 10.7, and amino acid identities ranging from 9 to 17%. Greater disparity in structure is observed for the ADAMTS13 CUB2 structure when compared with other CUB structures. This is due to the missing disulfide, the presence of the L17 loop α helix, and extensive divergence in the odd numbered loops.When CUB1 and CUB2 are superposed, their β strands and even numbered loops align well . In contWhen the ADAMTS13 CUB1-2 domain amino acid sequences are aligned with other tandemly arranged mammalian CUB domain proteins, the odd numbered loops  are more divergent (fig. S2). ADAMTS13 CUB1 and CUB2 have N-linked glycosylation sites on homologous loops . Glycosylation of these loops is not a conserved feature among tandemly arranged CUB domains, setting ADAMTS13 CUB domains apart (2+-binding site between the two longest odd numbered loops (fig. S2). However, the negatively charged residues on loops L5/L9 (CUB1) and L13/L17 (CUB2) required for Ca2+ coordination are not present in ADAMTS13 and bound Ca2+ is not observed in the structure (2+-binding CUB domains) that does not bind Ca2+  Arg1326, Glu1387, and Glu1389 locate to CUB2 β sheet #3, near the P2 pocket  residues Trp2 pocket . In addi2 pocket . On the istently  and previstently  .587-Thr593 and is hydrophobic in nature with residues Leu591 and Phe592 projecting outward. Leu637 on the adjacent L7 loop adds to this hydrophobic patch. Also, in loop L7, which spans residues Thr633-Pro638, are the negatively charged Glu634 and Asp635. Loop L9 spans residues Arg659-Arg670 and contains Arg660, Tyr661, and Tyr665, all previously implicated in CUB domain binding. Adjacent to this, loop L1 spanning Thr563-Arg568 contains basic Arg568 next to the L9 loop.The surface of the Spacer domain identified by the docking simulations to form interactions with CUB1-2 is formed by Spacer domain loops L1, L3, L7, and L9 that protrude from the end of the Spacer domain jelly roll fold , Leu637 (L7), and Leu668 (L9) in the Spacer domain interacts hydrophobically with Trp1245, Leu1248, and Trp1250 in CUB1. Last, we propose that the Spacer domain loop, L9, spanning Arg660-Tyr665 is accommodated ionically by the pocket formed by Arg1326, Arg1361, Glu1387, and Glu1389 in CUB2, with Tyr665 side chain predicted to make a cation-Pi interaction with Arg1326 (568 (L1) in the Spacer domain forming a salt bridge with Glu1389 in the CUB2 domain.On the basis of the highest scoring docking pose and our functional data, we propose an interaction in which Glu1 domain . At the  Arg1326 . There iThe 19 ADAMTS family proteases all have the same conserved MDTCS domain organization at their N termini. Thereafter, the number and identity of the C-terminal domains vary widely according to family member and functional subgroup  are particularly highly conserved between species, reflecting their importance in the overall fold of the tandem CUB1-2 domains (fig. S6). Ca2+-binding CUB domains often interact with their ligands through a conserved mechanism that relies upon the Ca2+-binding site in the odd numbered loops . Both CUB1 and CUB2 have the characteristic jelly roll fold of Caβ sheets  (31). Alnds Ca2+  and 3. Fnds Ca2+ . Notablyed loops  (31). Th1275 (that we substituted to Ser) is not present in other CUB domains. Previous studies have reported the ability of Cys1275 to undergo redox reactions that may regulate VWF function .In loop L9 in CUB1, the unpaired Cys1245, Trp1250, and Lys1252 in CUB1 and Arg1326, Glu1387, and Glu1389 in CUB2), which, when mutated, resulted in the near-complete disruption of Spacer-CUB binding  are in proximity to these two clusters. A fortuitous control for this assay was provided by one of the ADAMTS13 variants (R1219Q) that resulted in loss of binding of the 17G2 antibody and was therefore not activated, demonstrating the specificity of the assay for measuring disruption of the Spacer-CUB interaction   predicted to form direct interactions with the Spacer are perfectly conserved from humans to fish, which is a strong indication of functional importance . Our docked model reveals that this CUB2 site corresponds to the region that accommodates the well-described L9 Spacer domain loop containing Arg660, Tyr661, and Tyr665 that has been previously implicated in CUB domain binding . The conservation of the CUB1 site is also high—more so for the charged residues Lys1252 and Arg1272, but the hydrophobicity of Trp1245, Leu1248, and Trp1250 is generally well conserved , as are the reciprocal hydrophobic residues in the Spacer domain Leu591, Phe592, and Leu637 (fig. S7). Spacer-CUB–mediated global latency in ADAMTS13 is found in mammals, birds, reptiles, amphibians, and fish, despite appreciable variability in the number of intervening TSP repeats between the Spacer and CUB domains . This may therefore suggest that the enhanced enzymatic function of ADAMTS13 at pH 6 is not manifest by directly influencing Spacer-CUB binding site residues, but, rather in an indirect manner, through protonation of His residues throughout ADAMTS13 that, together, alter ADAMTS13 conformation.Given the evidence for involvement of these two clusters of amino acids in interacting with the Spacer domain, we performed further analyses using HADDOCK and ClusPro to generate a refined docking model. We selected the highest-ranking docking pose , which ar domain . Moreove1235 in CUB1 is quite well conserved between species (fig. S6) but is notably absent in mice, rats, canines, elephants, and some fish. An additional glycosylation consensus sequence is also found in loop L2 of CUB1 in some birds, reptiles, and amphibians, although it is unclear whether this site is occupied in these species (fig. S6). The glycosylation site on Asn1354 in CUB2 is poorly conserved between species, where it is either absent or potentially located in different positions on loop L13.Some studies have suggested that the N-linked glycans in the ADAMTS13 CUB domains may directly influence the Spacer-CUB interaction  by site-directed mutagenesis and verified by sequencing to prevent intermolecular disulfide bond formation. Primers used for site-directed mutagenesis were GTGGTGAGGCAGCGCTCCGGGCGGCCAGGAGGT and ACCTCCTGGCCGCCCGGAGCGCTGCCTCACCAC.The complementary DNA encoding the ADAMTS13 CUB1-2 domains (S1189-T1427) was cloned into the insect cell expression vector pMT-PURO-MBP. Primers used for amplification and cloning were CGCGCAGACTAATGCGGCCGCATCCAGTGCCTGTGGCAGG and TGGTGATGATGACCGGTACGCGTGGTTCCTTCCTTTCCCTTCCAG. ADAMTS13 CUB1-2 was cloned in frame with an N-terminal MBP tag and a 6xHis tag at the C terminus for purification. The surface-exposed unpaired cysteine, Cys−1) (Gibco) for 3 to 4 weeks. Cells stably expressing MBP-CUB1-2-His (C1275S) were expanded to 1 liter in EX-CELL 420 serum-free medium (Sigma-Aldrich)/puromycin (10 μg ml−1) in 2.5-liter flasks at 27°C/120 rpm to a cell density of 2 × 106 to 4 × 106 cells ml−1. To these, copper sulfate  was added to induce protein expression. Cells were cultured for a further 7 days, and media were harvested by centrifugation and filtration. Conditioned media were concentrated by tangential flow filtration using a 10-kDa filtration unit (Millipore) and dialyzed into 20 mM Hepes (pH 7.5), 0.5 M NaCl, 5 mM CaCl2, and 5 mM maltose. The dialyzed medium was applied to a HiTrap Chelating HP column  bound with Ni2+. The column was washed, and MBP-CUB1-2-His (C1275S) was eluted by stepwise increases in imidazole concentration . Fractions were analyzed by SDS–polyacrylamide gel electrophoresis and Coomassie staining, and the 100 mM imidazole elution fractions containing the highest concentrations of MBP-CUB1-2-His (C1275S) were dialyzed into 20 mM Hepes (pH 7.5), 150 mM NaCl, 5 mM CaCl2, and 5 mM maltose and further purified by gel filtration using a HiPrep 26/60 Sephacryl S-200HR column . The peaks containing monodisperse MBP-CUB1-2-His (C1275S) were concentrated using Amicon centrifugal filter (10-kDa cutoff) to 4 to 7 mg ml−1.This vector was transfected into Drosophila S2 cells using calcium phosphate, and stably transfected cells were selected using Schneider’s Drosophila medium (Lonza) containing 10% (v/v) fetal calf serum and puromycin (10 μg ml−1) and 1 μl of precipitant solution . For crystal freezing, the crystals were flash-frozen in a stream of nitrogen gas at 100 K. Diffraction data were collected on an Eiger2 X16M detector system at the I04 experimental station of the Diamond Light Source, UK. Data were processed and scaled using the autoPROC program. Further data analysis was carried out using CCP4 suite. The crystals belonged to space group P3221 and contained one molecule per asymmetric unit. Data collection statistics are summarized in Crystals of MBP-CUB1-2-His (C1275S) were grown using hanging-drop vapor diffusion at 20°C in 24-well VDX plates (Hampton Research). Initial crystallization conditions were established with screening kits from Hampton Research (Index) and from Molecular Dimensions  using sitting-drop vapor diffusion with mosquito crystallization robotics . For the optimal growth of MBP-CUB1-2-His (C1275S) crystals, each drop was prepared by mixing 1 μl of MBP-CUB1-2-His (C1275S) , which was used for the generation of all figures.To determine the structure of MBP fusion CUB1-2 domains, we used molecular replacement with Phaser (CCP4 suite) using the structure of MBP as a search model (PDB code: 3O3U). Clear electron density for β-strand CUB motifs was visible in the 29 positions). Using all the available templates for the Spacer, a variety of docking poses resulted in diverse combinations of the surfaces from the CUB1-2 domains and the Spacer domain. Many orientations could be ruled out based on the stereochemical position of the N and C termini. Only one orientation placed CUB1-2 consistently in the top ten scoring poses for all calculations, and this occurred in the top 10 p-scoring poses for all calculations. Docking simulations were also calculated with HADDOCK using a different approach by specifying residues in the Spacer domain for which experimental data had implicated involvement in the CUB interaction—i.e., Arg660, Tyr661, and Tyr665. These were defined as active residues. As no experimental data on interacting residues from the CUB1-2 structure were available, all surface-accessible residues were allowed to participate in docking.Three-dimensional models of the ADAMTS13 CUB1-2 domain complex with the ADAMTS13 Spacer domain were calculated using separate docking programs ClusPro 2.0 and HADDOCK 2.2  with a 6xHis tag fused to the C terminus has been described previously. DNA fragments containing single point and composite CUB1-2 domain mutations  were synthesized (Thermo Fisher Scientific) and subcloned into the wild-type ADAMTS13 vector using Mre I and Xba I restriction enzymes. Vectors were verified by sequencing. ADAMTS13 and ADAMTS13 mutants were transiently transfected into HEK293T cells using Lipofectamine and expressed in Opti-MEM (Invitrogen). After 3 days, conditioned media were harvested and centrifuged. Expression and secretion were analyzed by Western blotting using an anti-6xHis antibody. ADAMTS13 concentrations were measured by ELISA.2 (TBSC), and 1% bovine serum albumin (BSA) at 37°C for 15 min. Reactions were set up containing 0.45 to 0.6 nM ADAMTS13, or ADAMTS13 mutant, and 500 nM VWF96 in TBSC/1% BSA in the presence and absence of the activating anti–CUB1-2 monoclonal antibody 17G2 (10 μg ml−1). Ten microliters of reaction subsamples was stopped between 0 and 90 min with EDTA. The stopped subsamples were diluted to 0.75 nM VWF96 in TBS/1% BSA buffer and analyzed by VWF96 ELISA to quantify the concentration of uncleaved substrate. For this, anti-His G antibody (1.08 μg ml−1) (Invitrogen) was adsorbed onto 96-well microtiter plates in 50 mM sodium carbonate/bicarbonate (pH 9.6) overnight at 4°C. Wells were washed with TBS/0.1% Tween and blocked with TBS/3% BSA for 2 hours. Wells were washed, and a standard curve of purified full-length VWF96 (0 to 1.2 nM) diluted in TBS/1% BSA was added. In parallel, stopped samples were incubated at room temperature for 1 hour. After washing, peroxidase-conjugated anti–herpes simplex virus immunoglobulin G (0.5 μg ml−1) (Bethyl) diluted in TBS/1% BSA was added and incubated for 1 hour. Wells were washed, and 170 μl of SIGMAFAST o-phenylenediamine dihydrochloride peroxidase substrate (Sigma-Aldrich) was used for the detection. Color development was stopped using 2.5 M H2SO4 and measured spectrophotometrically at 492 nm.For kinetic analyses, wild-type and variant ADAMTS13 in conditioned medium and VWF96 were incubated separately in 20 mM tris (pH 7.8), 150 mM NaCl, 5 mM CaClP = 1 − exp(−1 × [ADAMTS13] × t × kcat/Km), where P is the fraction of VWF96 proteolyzed and t is the time in seconds. From this, the percentage change in catalytic efficiency, kcat/Km, in the presence of 17G2 was derived. Differences in percentage activation induced by 17G2 between wild-type ADAMTS13 and ADAMTS13 mutants were analyzed by one-way analysis of variance (ANOVA).The concentration of uncleaved VWF96 at each time point was measured from the standard curve, and from this, the fraction of substrate proteolyzed was calculated and plotted as a function of time. For each ADAMTS13 variant, the number of reactions performed is provided in the figure legends. The fold activation induced by incubation of the 17G2 antibody was determined using GraphPad software (Prism) by fitting the data from the time-course reactions into the equation,


The glass fiber reinforced polypropylene/AA2024 hybrid laminates (short for Al/Gf/PP laminates) as structural materials were prepared and formed by hot pressing. The synergistic effects of temperature and loading speed on the laminate deformation under tensile and bending conditions were investigated and analyzed in this study. In tension, stress–strain curves presented bimodal types effected by tensile rates and temperatures. The state of PP resin determines the mechanical behavior of the FMLs. The tensile rate has no effect on FML deformation without heating or over the melting point of PP resin (about 170 °C). The softening point of PP resin (about 100 °C) is characteristic temperature. When the temperature exceeds the softening point but does not reach the melting point, the tensile strength and elongation will demonstrate coordinated growth at a relatively high tensile speed. The efficiency of fiber bridging is affected significantly since the resin is the medium that transfers load from the metal to the fiber. Under bending, the curves presented a waterfall decrement with temperature increment. The softening point of resin matrix is the key in a bending process. When the temperature is near the softening point, deformation is sensitive to both the temperature and the loading speed to a certain extent. If temperature is lower than softening point, deformation is mainly guided by temperature. If the temperature is beyond the softening point, loading speed is in a leading position of deformation. The bending strength gradually increases with loading rate. By using these deformation characteristics, the deformation of the thermoplastic laminates can be controlled in stamping or other plastic forming processes for thermoplastic fiber metal laminates. Fiber metal laminates (FMLs) have developed rapidly in the last two decades as a family of hybrid materials consisting of bonded thin metal sheets and fiber/adhesive layers. This laminated structure provides the material with excellent fatigue, impact, and damage tolerance characteristics and a low density ,2,3,4,5.A thermoforming technique, such as hot stamping or hot pressing, has been used to process glass fiber reinforced polypropylene (PP). A hemispherical mold was used to form parts from pre-heated flat pre-consolidated laminates. Then, pre-consolidated laminates were heated and formed by contact heating above the PP melting temperature in a matched metal tool ,7,8,9,10Most investigations have only been concerned with the parameter study during a forming process, such as temperature, blank holder force, and punch rate ,18,19. HFor processing the thermoplastic FMLs, there were several raw materials and devices prepared. The glass fiber reinforced polypropylene (GFRP) prepregs were supplied from the Shanghai Genius Advanced Materials (Group) Co., Ltd.  and 2024-T3 aluminum alloy was used for the metal skin of the FMLs, which was supplied by Southwest Aluminum (Group) Co., Ltd. .The glass fiber reinforced polypropylene FMLs plates was 2/1 lay-up, which was a sandwich structure. Two prepregs were used as a monolithic core of the FMLs, which is named a fiber layer. Here, a typical cross-ply laminated GFRP was used to ensure structural symmetry. The ply sequence was (0°/90°) as shown in The tensile test was performed according to the standard of ASTM 3039-17. Specimens (200 mm × 20 mm) were prepared by waterjet cutting. The laser measuring instrument  was adopted to measure the deformation precisely. The three-point bending test was implemented according to the standard of ASTM D790-17. Samples were cut into 70 mm × 25 mm (length × width), in which 0° fibers were parallel to the length direction, while 90° fibers were perpendicular to it. The span to thickness ratio (L/H) was set as 16 for the bending test based on previous research result [The stress–strain curve tested in 1 mm/min stretching rate is shown in If the samples were stretched at 10 mm/min, the stress–strain curve became complete see . It can The stress–strain curve became the shapes as shown in For further visual comparison, three-dimensional tensile curves see  were useThe softening point of PP resin (about 100 °C) is characteristic temperature. When the temperature exceeds the softening point but does not reach the melting point, the tensile strength and elongation will demonstrate coordinated growth again at a relatively high tensile speed. Since the critical shear stress decreases and the crystal dislocation becomes relatively easy over 100 °C, the plasticity of metal improves obviously. For fiber layers, the state of PP resin is changed to a high-elastic state. According to the research of Guo et al. , the resWhen the temperature is close to the melting point of PP resin (170 °C), there are some jagged ripples in the stress–strain curves. For metal layers, dynamic aging strain occurred at that time, which is called the Portevin–Lechatelier (PL) effect . Based oIt also can be seen that loading rate and temperature control the deformation of FMLs synergistically. The FMLs demonstrate a rapid increase for the elastic-plastic deformation but a slower increase for the full plastic deformation if adopting 10.0 mm/min around room temperature. When approaching 100.0 °C, a remarkable decrease appears due to reaching the softening point. More specifically, the decrease of curve resulting from state transition. Stress transmission from metal skin to glass fiber through resin has been blocked suddenly. The synergistic effect of temperature and loading rate could be observed more clearly at the region where the temperature is between the softening point and the melting point of PP resin. In addition, it can be seen that the sensitivity of Al/Gf/PP laminates to temperature and loading rate is different. The sensitivity to temperature is higher than loading rate. The influence of temperature is mainly realized by changing the state of PP resin.The synergistic effect of temperature and loading rate can be further proved by the failure modes of FMLs see . The faiThe bending test results under different load conditions are shown in Meanwhile, the strength is absolutely high at room temperature. When the temperature is close to the softening point of PP resin, the bending strength decreases greatly. If the temperature exceeds the softening point but does not reach the melting point, the strength is in a stable state while the specific elongation increases. It can be seen that the softening temperature of PP resin is a clear cut-off point. Once the resin softens, the resistance to deformation decreases sharply. The deformation behavior is sensitive to loading speed when the resin is just in an elastic state.Comparing the results curves shown in If the temperature rises close to softening point of PP resin, the deformation reaches to the second stage. The stiffness decreases significantly, and the elongation increases. From the perspective of metal layers, the upper layer is subjected to the action of compressive stress, which can effectively inhibit the intergranular deformation, at the same time eliminating some micro damage caused by plastic deformation. Moreover, the matrix cannot provide enough support since it reaches an elastic state.When the temperature is closer to melting point, there is a smooth deformation surface. The resin changes to the viscous state. The matrix can only transmit a part of the stress and bear shear stress. The FMLs can still withstand a bending load by metal layers.It can also be seen that the curves in the three-point bending vary as a waterfall type with temperature. In the range from room temperature to softening temperature (100 °C), the stiffness and strength of the FMLs significantly reduce with the increment of temperature. When the temperature is near the softening point, deformation is sensitive to both the temperature and the loading rate to a certain extent. As the temperature rises, the bending strength decreases. However, with the increase of loading rate, the stress increases slightly due to strain hardening. The bending strength increases significantly if adopting a high loading rate due to the working hardening of aluminum metal skin. If the temperature is lower than the softening point, deformation is mainly guided by temperature. If temperature is beyond softening point, loading rate is in a leading position of deformation. The bending strength gradually increases with increasing loading rate. Thus, the softening point of resin matrix is the key if a part of FMLs need to be formed by the bending process.The failure forms were photographed by optical microscope to prove the analysis, as shown in In mode I, the fiber layers always behave elastically, and the metal layers are elastoplastic. The softening point of PP resin (about 100 °C) is characteristic temperature. When the temperature is over the softening point, both glassy state resin and high-elastic state resin exist. For fiber layers, the resin matrix deforms greatly under shear when the resin softens . MeanwhiIn mode II, the temperature reaches the melting point of PP resin. The fiber arrangement is changed with the overflow of melted PP resin without bridging effect. The metal layers are still elastoplastic, but the fiber layers cannot bear the external load. The resin matrix is in a viscous state at this time. The fiber can be squeezed under external force, leading to fiber sliding. The failure of FMLs depends on the ductile fracture of metal layers. Therefore, the melt point of PP resin matrix is a characteristic temperature that controls the tensile behavior of Al/Gf/PP laminates.In this study, the synergistic effect of temperature and loading rate on the Al/Gf/PP laminate deformation could be concluded. The softening point and the melt temperature of PP matrix are two critical points for deformation. Between the two points, the deformation of the material is controlled by loading rate. Meanwhile, loading rate also controls the deformation gradient. When the resin is in a high-elastic state, the loading rate should be controlled in a relative high range. At the moment, a flat deformation surface emerges. Delamination and matrix cracks did not appear. If the forming temperature is more than the melt temperature of resin, the deformation is hard to control due to resin flow. In a word, the temperature can affect the deformation range as a main factor. Then, the loading rate can control the deformation precisely in the range. Therefore, the Al/Gf/PP laminate should be formed between the softening point and melt point through controlling the loading speed.


UIATS recommended treatment in n = 52, 25% cases (TP), was inconclusive in n = 93, 44% (excluded), and recommended observation in n = 67, 32% (FN). Based on these data, the UIATS showed a sensitivity of 44% (CI 35–53%). The UIATS exhibits rather low sensitivity for detecting aneurysms at risk of rupture.To evaluate if the unruptured intracranial aneurysm treatment score (UIATS) is a sensitive tool to detect aneurysms at risk of rupture, we conducted an a posteriori retrospective study on ruptured intracranial aneurysms. We performed a retrospective analysis of adult patients admitted to our center from January 2010 to April 2016 with aneurysmal subarachnoid hemorrhage. The UIATS was applied to all ruptured aneurysms. Patients for whom the UIATS recommended treatment were labeled as “true positives,” whereas patients for whom the UIATS recommended observation were labeled as “false negatives.” Patients for whom the UIATS was inconclusive were excluded from the final analysis. Based on the UIATS recommendation, a sensitivity analysis was performed. A total of 262 patients with aneurysmal subarachnoid hemorrhage were screened. Of these, 212 were included in our analysis. Median age was 53 years (23–90). Most patients were females ( Unruptured intracranial aneurysms (UIA) have an approximate prevalence of 3% worldwide , and theThe most relevant studies to this matter are the International Study of Unruptured Intracranial Aneurysms (ISUIA)  from NorTaking into consideration these risk factors, clinicians have performed prophylactic treatment of UIA in order to avoid the devastating consequences of aSAH, in spite of the risks associated to therapy and the lack of evidence for a clinical benefit . A meta-The unruptured intracranial aneurysm treatment score (UIATS)  was publ.In order to assess whether the UIATS is a sensitive enough tool to identify aneurysms at risk of rupture, we evaluated a cohort of patients with aSAH with the UIATS a posterioriWe performed a retrospective analysis of consecutive adult patients admitted to our center from January 2009 to April 2016 with aSAH. Inclusion criteria comprised (a) age over 18 years and (b) aSAH caused by ruptured saccular aneurysms of the anterior or posterior circulation, confirmed by computed tomography angiography (CT-A) and/or digital subtraction angiography (DSA). Patients harboring mycotic, traumatic, fusiform, or dissecting aneurysms were excluded. Further exclusion criteria were insufficient data on patient files to assess the risk factors comprised in the UIATS.The UIATS was applied to all ruptured aneurysms (RA). In patients with multiple aneurysms, the lesion considered to be responsible for the aSAH was the only one evaluated by means of UIATS. The risk factors considered in the UIATS are summarized in Table Based on the UIATS recommendation, a sensitivity test was performed. Sensitivity was defined as the ability of the UIATS to identify aneurysms at risk of rupture by recommending treatment in a cohort with proven aSAH. To estimate it, the following equation was employed: sensitivity = TP/(TP + FN).n = 134, 63%), with an equal distribution between low-grade and high-grade hemorrhages .A total of 262 patients with SAH were screened. Of these, 212 were included in our analysis. Of the 50 patients excluded, one had a flow-associated aneurysm in the setting of an arteriovenous malformation, one had insufficient data, and 48 had either dissecting or fusiform aneurysms. Mean age was 53 years (23–90). Most patients were females . No patients were of Japanese, Finnish, or Inuit origin. Furthermore, only one patient had a medical history of adult polycystic kidney disease. Illicit drug abuse were present in a minority of patients: active cigarette smoking was observed in n = 31, 15%, while current alcohol or drug abuse was reported in n = 14, 7%, and n = 3, 1%, respectively. Aneurysm multiplicity was seen in n = 67, 32%. Most patients had a life expectancy > 10 years before aSAH . For a detailed summary of patient-related risk factors, see Table The most common patient-related risk factor observed in our cohort was pre-existing arterial hypertension n = 9, 43%. Non = 75, 35%), followed by the middle cerebral artery (MCA) . Aneurysms in the posterior circulation were responsible for a minority of aSAH . The most frequent aneurysm-related risk factors observed in our cohort were irregularity or lobulation , and aspect ratio > 1.6 or size ratio > 3 . Interestingly, aneurysms were rather small: most of them were between 4.0 and 6.9 mm in diameter , followed by those between 7.0 and 12.9 mm , and those < 3.9 mm . Further aneurysm-related risk factors are summarized in Table Aneurysms were predominantly located in the anterior communicating artery (ACOM) n = 75, 5%, follon = 52, 25% cases (TP) was inconclusive in n = 93, 44% (excluded), and recommended observation in n = 67, 32% (FN). The distribution of the UIATS results is summarized in Fig. UIATS recommended treatment in One of the most complex questions currently faced by cerebrovascular surgeons is which UIA should be treated. To date, there are no unequivocal criteria by which to estimate the risk of rupture of a given UIA, since several factors can interact and determine the natural history of a lesion.In 2014, Greving et al.  publisheBijlenga et al.  recentlyHowever, the PHASES score has undergone heavy criticism because certain groups of patients were underrepresented. For example, smoking , 12, 27 In a recent publication by Hilditch et al. , the PHAThe UIATS was developed shortly after the PHASES score as a multidisciplinary consensus model, in which patient-related, aneurysm-related, and treatment-related risk factors were considered in quantitative fashion. Unlike the PHASES score, the UIATS took into consideration treatment-related risk factors, as well as aneurysm-related and patient-related risk factors, thus providing a more comprehensive assessment of all the variables that might influence treatment decision-making in UIA. Nevertheless, its aim was not to provide a prognostic nor a predictive model for UIA rupture, but a reflection of contemporary practice in UIA management and guidance to clinicians treating patients with UIA.In October 2017, Ravindra et al.  publisheSimilarly, our group published in February 2018 [. While the methodology of our study was rather simple, it provides understandable data in regard to a straightforward question: could the UIATS correctly identify aneurysms at risk of rupture? Our study suggests that the UIATS does not have sufficient sensitivity to be considered a reliable tool in UIA decision-making. In almost half of our patient cohort, the UIATS failed to provide a recommendation (inconclusive cases). Additionally, almost a third of the patients were categorized as FN, since the UIATS recommended observation. Cumulatively, almost 75% of our patient cohort would have been erroneously classified. Had these patients presented incidentally before rupture, they could have succumbed to a fatal aSAH due to misclassification.The present study is the first one to assess the UIATS’ ability to identify intracranial aneurysms at risk of rupture a posterioriOf note, most of the ruptured lesions in our cohort exhibited a rather small size, which might have contributed to a lower UIATS and thus their misclassification as aneurysms amenable to observation. Furthermore, most patients were female, a risk factor for UIA rupture well described in the literature , 13, 29 As noted by Indrayan and Malhotra , a scoriFahed et al.  offer inIn the last decade, hemodynamic parameters have emerged as potential markers of rupture risk in UIA. Some of these parameters include wall shear stress (WSS) and oscillatory shear index (OSI), which can be measured by computational fluid dynamics (CFD) . Two of Our study is retrospective in nature with a relatively small patient population. The retrospective design renders the study subject to several biases, in particular, data quality assurance. Risk factors contained in the social history, such as tobacco or alcohol consumption, might not have been accurately documented. This, in turn, might have skewed the UIATS towards observation instead of treatment. A larger, prospective cohort might have yielded different results, possibly in greater accordance with the UIATS.On the other hand, because of the methodology of our study, predictive values and specificity could not be calculated, as the entire cohort was considered as “diseased.” The former would presuppose a disease prevalence of 100%, which does not reflect the real prevalence of aSAH or UIA. Therefore, the estimation of predictive values and accuracy cannot be conducted in a reliable fashion. While this is also a potential limitation of the study, our results serve to illustrate how fallible the UIATS can be.Treatment decision-making in patients with UIA remains difficult and controverted. To date, no prospective cohort studies exist to unequivocally answer the question of which UIA should be treated in order to prevent devastating aSAH. In such a dubious scientific environment, the UIATS provides a quantification of expert-assessed risk factors for UIA rupture. While useful when considering all the variables that should determine UIA treatment, the UIATS is not an empiric, mathematical model. Consequently, the UIATS should be regarded as a harmonized expert opinion on a complex subject matter, not fact. The authors thus recommend the use of UIATS as an adjunct in UIA treatment decision-making, but not as a stand-alone tool.


Herein, Co‐MnO2 has excellent electrochemical properties in tests as the cathode electrode of sodium‐ion batteries and potassium‐ion batteries. The rate performance remains at 50.2 mAh g−1 at 200 mA g−1 for sodium‐ion batteries. X‐ray diffraction (XRD) is utilized to evaluate the crystal structure transition from Co0.2‐MnO2 to NaMnO2 with discharge to 1 V, proving that Co‐doping does indeed facilitate the acceleration of ion transport and support layer spacing to stabilize the structure of MnO2. Subsequently, highly conductive (0.0848 S cm−1) gel‐type supercapacitors are prepared by combining Co0.2‐MnO2, potassium hydroxide (KOH), and poly (PVA) together. Co0.2‐MnO2 provides capacitive behavior and strengthens the hydrogen bonds between molecules. KOH acts as an ion crosslinker to enhance hydrogen bond and as electrolyte to transport ions. 5 wt% Co0.2‐MnO2@KOH/PVA has superb mechanical endurance, appreciable electrical conductivity, and ideal capacitive behavior. The quasi‐solid‐state supercapacitor demonstrates stabilized longevity (86.5% at 0.2 mA cm−3 after 500 cycles), which can greatly promote the integration of flexible energy storage fabric devices.Manganese dioxide (MnO 0.2‐MnO2, and the mechanical property with capacitance of 5 wt% Co0.2‐MnO2@KOH/PVA. 5 wt% Co0.2‐MnO2@KOH/PVA has the largest tensile strength and compressive resistance. The high volume capacitances and energy density of quasi‐solid‐state supercapacitors provide direction for the next generation of wearable device applications.This paper reports the Na‐ion and K‐ion storage mechanism of Co Whereas, MnO2‐based materials exhibit serious performance degradation, which is affected by their low electronic conductivity (≈10−5 to 10−6 S cm−1), slow diffusion rate of ions, narrow tunnel size, and dramatic structural change during the charge/discharge process. Doping heteroatoms, on the one hand, can optimize the electronic structure of MnO2, thereby shortening ion transfer routes and improving its constitutive conductivity; on the other hand, can play a role in extending and supporting layer spacing to prevent structural collapse.Among various active materials used in sodium‐ion batteries (SIBs), potassium‐ion batteries (PIBs), and supercapacitors, manganese dioxide  (PVA), a kind of polymer, can be used to manufacture a nontoxic, biodegradable, and deformable matrix. However, there are many problems needed to be solved urgently, such as poor mechanics properties, and inferior ionic conductivity (10−5–10−8 S cm−1).Actually, doping inorganic substances, like borax and FeCl3, can not only improve the conductivity, but also cross‐link the PVA to form a polymer network and then improve the mechanical properties.Furthermore, MnOlar life.4 The 2, and the mechanical property with capacitance of Co‐MnO2@KOH/PVA. Minutely, Co0.2‐MnO2 has a capacity of 71.8 mAh g−1 after 100 cycles in SIBs. A series of tests has been used to elucidate the electrochemical kinetics. The X‐ray diffraction (XRD) reveals that the characteristic peak of NaMnO2 appears. 5 wt% Co0.2‐MnO2@KOH/PVA has the largest tensile strength of 4.25 MPa and compressive resistance of 4.7 MPa as the strain increases to 70%. The volume capacitances of quasi‐solid‐state supercapacitors are 6.86, 6.44, 4.2, 3.1, and 1.8 mF cm−3 at current densities of 0.1, 0.2, 0.3, 0.5, and 1 mA cm−3.Herein, we report the Na‐ion and K‐ion storage mechanism of Co‐MnO22.1Figure 2 was synthesized by a one‐step hydrothermal process. In order to explore the crystal structure and composition of Co0.2‐MnO2, X‐ray diffraction (XRD) and X‐ray photoelectron spectroscopy (XPS) spectra were performed. Figure 0.2‐MnO2 and MnO2 nanorods. All diffraction peaks of Co0.2‐MnO2 agree well with MnO2 (PDF#01‐0799) without impurity peak. Compared with pure MnO2, Co0.2‐MnO2 shows a characteristic peak of (110) with a higher intensity and sharper peak shape, which confirms that Co not only supports and widens the layer spacing but also contributes to the exposure of a (110) crystal plane. Subsequently, XPS is used to explore the chemical compositions and valence states of Co0.2‐MnO2. The existence of Co can be proved by the appearance of Co 2p peaks in a full spectrum of Co0.2‐MnO2  images , scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The surface area of Cos Figure  show tha2.22 cathode were analyzed by 2032 cells with the range of 1.0–3.8 V for SIBs. All electrodes in Figure −1 and then cycle at a constant current density of 100 mA g−1. Co0.2‐MnO2 has a discharge capacity of 71.8 mAh g−1 after 100 cycles with a coulombic efficiency (CE) approaching 100%, whereas, Co0.1‐MnO2, Co0.3‐MnO2, and MnO2 show poor stability  throughout the charge–discharge cycles. The fact indicates that the doping of Co can significantly improve the electrochemical performance of MnO2‐based materials and Co0.2‐MnO2 possesses the best reversible capacity and structural stability than any other material. Figure −1 with current densities of 10, 20, 50, 75, 100, and 200 mA g−1. The performance remains at 71.6 mAh g−1 when the current density backs to 10 mA g−1. Figure 0.2‐MnO2 at different current densities. The similar curves prove the splendid reversibility and stability of Co0.2‐MnO2 once again. The performance of this work is better than that of other materials, the comparison diagram is shown in Figure The electrochemical performances of Co‐MnOmaterial.11 Fig−1) have been attained to elucidate the electrochemical kinetics. As shown in Figures  The pseudocapacitive contribution ratios in Figure −1, further verifying that the material has an excellent fast charging/discharging ability. In addition, Figure 0.1‐MnO2, Co0.2‐MnO2, Co0.3‐MnO2, and undoped MnO2, as the active material. The values of charge‐transfer resistance (Rct) for Co0.1‐MnO2, Co0.2‐MnO2, Co0.3‐MnO2, and undoped MnO2 electrodes are 2645, 1571, 2586, and 4749 Ω, respectively. The smaller charge‐transfer resistance (Rct) in the high frequency region indicates that doping with Co enhances sodium intercalation near the electrode/electrolyte interface. The real part (ZRe) in the low‐frequency range is linear against the square root of the angular frequency  in Figure 0.2‐MnO2 is the lowest, indicating its fast sodium ions diffusivity, which in turn illustrates the best rate performance. Just as we predicted, the doping of Co reorganizes the electronic distribution of MnO2, promoting the Na+ adsorption and the reaction kinetics.To interpret the prominent electrochemical properties, the cyclic voltammetry (CV) curves  appear and the characteristic peaks of MnO2 gradually decrease with discharge to 1 V. The SEM in Figure 2. The peaks of MnO2 will reappear when charging to 3.8 V, as shown in Figure In addition to investigating the kinetic properties of SIBs, the redox peak of the CV diagram Figure  can be u0.2‐MnO2 not only has an excellent performance in SIBs, but also has outstanding results in PIBs. As shown in Figure −1 after 100 cycles at 100 mA g−1. The rate performance in Figure 0.2‐MnO2 cathode can stay at 47.6 mAh g−1 at 200 mA g−1. The CV curves in Figure 2.In fact, Co2.30.2‐MnO2, with stable structure and fast transmission speed, could also be used to make supercapacitors. Flexible supercapacitors can be prepared by combining elastic material with manganese dioxide. Poly  is a water‐soluble polymer, containing a mass of hydroxyl groups. KOH, as crosslinking agents, can enhance the mechanical properties of PVA by increasing the extent of intermolecular cross‐linking and the extent of network entanglement. As shown in Figures VO‐H shift from 3282 to 3255 cm−1 of 1 m, 2 m, and 2.5 m KOH‐PVA, indicating the hydrogen bonds are gradually increasing. The pictures of these four materials , when the content of Co0.2‐MnO2 is 5 wt% and KOH is 2 m. Moreover, it is obvious from the circuit experiment  curves area, that is, has the highest specific capacitance. The reason is that on the one hand, Co0.2‐MnO2 owns the excellent capacitive performance, and on the other hand, it has the highest content of Co0.2‐MnO2 in 5 wt% Co0.2‐MnO2@KOH/PVA fiber. Figure −1 of 5 wt% Co0.2‐MnO2@KOH/PVA, revealing ideal capacitance characteristics. In addition, a 5 wt% Co0.2‐MnO2@KOH/PVA electrode still maintains a rectangle for all CV curves at low rates, indicating that the fiber has fast electronic transfer. The GCD curves of 5 wt% Co0.2‐MnO2@KOH/PVA at different current densities in Figure −3 at 0.1, 0.2, 0.3, 0.5, and 1 mA cm−3. The energy densities of material are 0.56, 0.54, 0.53, 0.50, and 0.46 μWh cm−3 when the power densities are 0.025, 0.05, 0.075, 0.125, and 0.25 mW cm−3. As shown in Figure As shown in s Figure . 5 wt% Ctransfer.16 The0.2‐MnO2@KOH/PVA gel fibers were encapsulated parallelly in 1 m KOH‐PVA acting as electrolyte and separator to evaluate the electrochemical properties of a quasi‐solid‐state asymmetric supercapacitor in Figure −, and Co0.2‐MnO2 gives the material robust flexibility to facilitate its stretching and bending. The contact angle is greater than 120° . Afterwards, 5 wt% Co0.2‐MnO2 combining with 2 m KOH‐PVA has excellent mechanical stability and conductivity to be used in flexible electronic devices. Quasi‐solid‐state supercapacitors possess superior energy densities and a stable life of 86.5%, which provides direction for the next generation of wearable device applications.In summary, Co substitution can improve the electron transport, increase the intrinsic conductivity of MnO44·H2O, Macklin, 99.9%), ammonium persulfate ((NH4)2S2O8, Macklin, 99.0%), cobalt nitrate, hexahydrate (Co(NO3)2·6H2O, Macklin, 99%), poly 1799 , and potassium hydroxide , all reagents were used directly without purification.Manganese sulfate, monohydrate 2S2O8, and the proper amount of Co(NO3)2·6H2O  were dissolved in deionized water and then stirred 10 min at 20 ℃ to form a black solution. Next, the solution was transferred to a Teflon‐lined autoclave at 180 ℃ for 24 h. Finally, the Co‐MnO2 was gathered by filtration and washing it several times, followed by a calcining process at 300 ℃ for 2 h. According to the different content of Co(NO3)2·6H2O, the materials were named Co0.1‐MnO2, Co0.2‐MnO2, Co0.3‐MnO2 in turn.0.01 mol MnSO0.2‐MnO2 with different mass fractions  were dispersed in 20 mL deionized water, in which PVA powders were added at 90 ℃ and stirred for 2 h . Next, different concentrations of KOH  were added with intense agitation to form a viscous liquid. Finally, the liquid was injected into a silicone tube with a diameter of 3 mm, followed by three cycles of freeze‐thawing (−18 ℃ for 5 h and at 25 ℃ for 2 h), called 1 wt% Co0.2‐MnO2@KOH/PVA, 2 wt% Co0.2‐MnO2@KOH/PVA, and 5 wt% Co0.2‐MnO2@KOH/PVA. In addition, PVA hydrogels (12 wt%) with different concentrations of KOH  were prepared, named 1 M KOH/PVA, 2 M KOH/PVA, and 2.5 M KOH/PVA, successively.Com KOH, 5 wt% Co0.2‐MnO2, diameter of 1 mm) were paralleled together and then coated with PVA electrolyte  to form fiber hydrogel supercapacitors (diameter of 3 mm).Two fibers (2 m Na2SO4 in ethylene carbonate (EC)/dimethyl carbonate (DEC)  with an addition of 2% fluoroethylene carbonate (FEC), and 1 m KFSI in ethylene carbonate (EC)/dimethyl carbonate (DEC)  for SIBs and PIBs, respectively. Cycling and rate performance were tested by LAND CT‐2001A battery‐test instrument in a range of 1–3.8 V. CHI660E (China Brilliance Shanghai) electrochemical workstation tested cyclic voltammetry (CV) and electrochemical impedance spectroscopy measurement (0.01 Hz to 100 kHz). The calculation formula of pseudocapacitance: the correlation between peak current (I) and scan rate (v): i  =  bav. The capacitance‐ and the diffusion‐control contribution can be distinguished by: i (V) = k1 v + k2v1/2.Electrochemical performance of SIBs/PIBs was tested by CR2032 cells with Na/K metal foil as the counter electrode and glass fiber (GF/F) as separator. The working electrode was obtained from a mixture of active materials, super P and PVDF (weight ratio: 7:2:1), coated onto Al foil, and then dried at 60 ℃ overnight. The corresponding electrolyte was 1 + (DNa+) could be decided by: DNa+=0.5R2T2/A2n4F4C2σ2·R,T,A,n,F, and C are constants, it can be seen that σ is inversely proportional to the diffusion coefficient (DNa+). σ (Warburg coefficient) can be determined by the slope of the fitting linear of ZRe‐ω−1/2:ω  =  2Πf, ZRe =  R + σω−1/2.The diffusion coefficient of NaCv) was computed by the equation: CV =  I  ×  t  ×  U−1  ×  V−1. I, t, U, V stand for the current, discharge time, potential window, and the volume of the Co‐MnO2@KOH/PVA fiber hydrogels, severally. The volume energy density (E) and volume power density (P) were estimated by the following equation: E  =  CU2  ×  2−1  ×  3600−1 and P  =  3600E  ×  t−1.For supercapacitor, CV, electrochemical impedance spectroscopy and galvanostatic charge–discharge measurements of hydrogels were performed by using an CHI660E electrochemical workstation (−0.2–0.4 V). The volume capacitance Cv was com2 powder. SEM (JEOL JSM‐7500F) and TEM  were carried out to characterize the morphology and structural characteristics of Co‐MnO2 powder. XPS was applied to analyze the valence of Mn, O, C, and Co elements. Specific surface area analyzer (Mike 2020 HD88) was used to survey Brunner–Emmet–Teller (BET) surface area. spectrophotometer  was applied to explore the Fourier transfer infrared spectroscopy (FTIR) spectra of the hydrogels. Mechanical testing machine (AGS‐X 1kN) was applied to the compression test and tensile test of the hydrogels.XRD (Shimadzu XRD‐6000) was used to characterize the crystal structure of the Co‐MnOThe authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Five different sacral fracture fixation methods were compared using finite element (FE) analysis to study their biomechanical characteristics.Denis type I sacral fractures were created by FE modeling. Five different fixation methods for the posterior pelvic ring were simulated: sacroiliac screw (SIS), lumbopelvic fixation (LPF), transiliac internal fixator (TIFI), S2-alar-iliac (S2AI) screw and S1 pedicle screw fixation (S2AI-S1) and S2AI screw and contralateral S1 pedicle screw fixation (S2AI-CS1). Four different loading methods were implemented in sequence to simulate the force in standing, flexion, right bending and left twisting, respectively. Vertical stiffness, relative displacement and change in relative displacement were recorded and analyzed.As predicted by the FE model, the vertical stiffness of the five groups in descending order was S2AI-S1, SIS, S2AI-CS1, LPF and TIFI. In terms of relative displacement, groups S2AI-S1 and S2AI-CS1 displayed a lower mean relative displacement, although group S2AI-CS1 exhibited greater displacement in the upper sacrum than group S2AI-S1. Group SIS displayed a moderate mean relative displacement, although the displacement of the upper sacrum was smaller than the corresponding displacement in group S2AI-CS1, while groups LPF and TIFI displayed larger mean relative displacements. Finally, in terms of change in relative displacement, groups TIFI and LPF displayed the greatest fluctuations in their motion, while groups SIS, S2AI-S1 and S2AI-CS1 displayed smaller fluctuations.Compared with SIS, unilateral LPF and TIFI, group S2AI-S1 displayed the greatest biomechanical stability of the Denis type I sacral fracture FE models. When the S1 pedicle screw insertion point on the affected side is damaged, S2AI-CS1 can be used as an appropriate alternative to S2AI-S1.The online version contains supplementary material available at 10.1186/s13018-021-02805-8. Sacroiliac screws (SIS), lumbopelvic fixation (LPF) and transiliac internal fixators (TIFI) have been widely used clinically as the three conventional methods of posterior pelvic ring injury treatment. Nevertheless, each method has limitations –5. SacroTo address the problems caused by the protrusion of the iliac screws, the S2-alar-iliac (S2AI) technique has been proposed to replace the iliac screw in lumbosacropelvic fixation , 7. The For Denis type I sacral fractures, the lumbosacral joint is considered to be preserved and therefore has a certain degree of stability . The purThe aim of this study was to investigate the biomechanical stability of S2AI-S1, S2AI-CS1, SIS, LPF and TIFI for the treatment of non-osteoporotic sacral fractures (Denis type I) through finite element (FE) analysis.u) of cortical bone, cancellous bone, articular cartilage, intervertebral and interpubic disk tissue, and titanium metal were derived from the literature [CT data of the lumbar spine and pelvis were collected from a healthy male volunteer . The CT imaging data were processed using Mimics 21.0 , Geomagic Studio 2013  and Solidworks 2017  software to construct a model of the lumbar spine and entire pelvis. The interpelvic ligaments included iliolumbar ligament, anterior sacroiliac ligament, long posterior sacroiliac ligament (LPSL), short posterior sacroiliac ligament (SPSL), interosseous sacroiliac ligament, sacrospinous ligament, sacrotuberous ligament, superior pubic ligament and arcuate pubic ligament, all of which were simulated as spring structures in the finite element analysis software, ANSYS 17.0 . The values for Young’s modulus (MPa) and Poisson's ratio  were obtained, respectively, by grid line segmentation. The ligaments were injured as follows: Denis type I sacral fracture accompanied injuries of the LPSL and part of the SPSL. The anterior pelvic ring destruction resulted in injuries of the interpubic disk, superior pubic ligament and arcuate pubic ligament.The anterior pelvic ring was fixed with a plate, and the methods of fixing the posterior pelvic ring were as follows: In the SIS group, a half-thread hollow screw (7.3 mm × 75 mm) was placed horizontally into the S1 segment; in the S2AI-S1 and S2AI-CS1 groups, the S2AI screw (7.5 mm × 80 mm) was inserted according to the method in study  and thenA standing posture with two legs was simulated as the boundary condition: the acetabulum on both sides was fixed in all directions. A vertical force of 500 N  was applThe vertical stiffness of each group was calculated based on the vertical displacement of the center point of the upper surface of S1 . Four pairs of points Fig.  on both The number of elements used in the FE models of the SIS, LPF, TIFI, S2AI-S1 and S2AI-CS1 groups were 766,579, 772,157, 754,849, 751,032 and 757,516, respectively. A mesh convergence study was conducted and the appropriate mesh resolution for the FE model was determined from the influence of the maximum von Mises stress on bone. Doubling the number of elements in the FE models changed the maximum von Mises stress on the bone by 2.22%, 1.85%, 2.07%, 1.95% and 1.99% for the SIS, LPF, TIFI, S2AI-S1 and S2AI-CS1 groups, respectively, indicating that the original mesh size in the FE models satisfied the accuracy requirements of the analysis.Under 500 N vertical loads, the FE predicted maximum compressive displacement (0.640 to 1.136 mm) of the intact pelvic model was consistent with the corresponding experiment-measured peak compressive displacements (0.973 to 1.550 mm) reported by Comstock et al.  under thZ-axis) of the center point of the upper surface of the S1 vertebral body of the five groups in descending order were TIFI, LPF, S2AI-CS1, SIS and S2AI-S1  of the five groups in descending order were TIFI, LPF, SIS, S2AI-CS1 and S2AI-S1 (except that the mean RD of LPF in flexion and left twisting was greater than in TIFI) Fig. a–d. The Compared with standing, the change in relative displacement of the SIS, S2AI-S1 and S2AI-CS1 groups for three different movements fluctuated less than in LPF and TIFI. For the LPF group, the change in relative displacement during flexion was larger, while in right bending and left twisting the changes were smaller. For the TIFI group, the change in relative displacement was larger in flexion and left twisting, while it was smaller in right bending Table .Table 3CThe incidence of non-osteoporotic sacral fractures has been reported as 2.1 cases per 100,000 of the population and usually occurs when young individuals have a traffic accident or fall from a height . Due to P < 0.005), respectively. Although the Denis type I fracture model was used in this study, stability in the SIS group was higher than in the unilateral LPF group. This points to the consistency between the simulation results and biomechanical experiments. In an FE analysis study, Song et al. found that unilateral LPF could not provide sufficient horizontal and rotational stability for patients with unilateral sacral fractures [In the biomechanical experiment of artificial bone models , the posterior pelvic ring was fixed with SIS and unilateral LPF, respectively. At 4000 cycles (500 N), the relative displacements of the SIS group and the unilateral LPF group were 4.02 ± 1.18 mm and 15.59 ± 4.00 mm   suggest Nevertheless, potential limitations related to this study should be noted. First, these simulation results are only based on a FE analysis of static linear displacement, while screw loosening was not considered. The stability of S2AI-S1 needs to be further verified by cyclic loading experiments on cadaver bone models. Second, the screw in this experiment used simplified processing to reduce the calculation time and analysis error due to stress concentration. However, to obtain accurate stress distribution on the screw and the bone around the screw, the screw thread should be considered in the FE model . Third, Compared with SIS, unilateral LPF and TIFI, S2AI-S1 displayed the best biomechanical stability of the Denis type I sacral fracture FE models. When the S1 pedicle screw insertion point on the affected side is damaged, S2AI-CS1 can be used as a appropriate alternative to S2AI-S1.Additional file 1: The calculation formula of relative displacement and change in relative displacement.Additional file 2: The relative displacement in standing.Additional file 3: The relative displacement in flexion.Additional file 4: The relative displacement in right bending.Additional file 5: The relative displacement in left twisting.


Defining the disrupted mothering would contribute to developing strategies to support mothers with breast cancer. The aim of this study was to analyze the concept of mothering disruption using a hybrid model.The Hybrid method for concept analysis was implemented consisting of three phases: theoretical, fieldwork, and final analysis. In the theoretical phase, the literature was searched using electronic databases including PubMed, ScienceDirect, Scopus, ProQuest, Google Scholar, CINAHL, Wiley, Ovid, Magiran, and SID from 2000 to 2020. Any quantitative or qualitative studies published in English or Persian, which were focused on mothering disruption in mothers with breast cancer were included in the study. In the phase of fieldwork, 20 mothers were interviewed to explore the aspects of mothering disruption. The interviews were transcribed and analyzed with conventional content analysis. In the final phase, an overall analysis of the two previous phases was performed.In the theoretical phase, the following attributes were determined: “disturbance in maternal identity and roles”, “maternal insensitivity and unresponsiveness: disconnection physically and psychologically”, “the career disruption process” and “biographical disruption”. The fieldwork phase explored three themes including “the unbalance between multiple roles”, “role failure”, and “reduced maternal sensitivity”. The final synthesis yielded that the main integrated elements of mothering disruption are “disease as threating maternal role and identity”, “inability to interpret and respond to child behaviors and needs”, and “support for transitioning from being patient toward maternal competency”.With a deeper understanding of the term ‘disrupted mothering’ or ‘mothering disruption’, healthcare providers will have a foundation to improve cancer care, deliver effective communication and help such mothers cross this disruption and achieve restoration of their mothering role. Future research is needed to validate this concept and explore connections with health outcomes.The online version contains supplementary material available at 10.1186/s12905-021-01346-w. Identitnt child . Mothersnt child .Disrupted mothering based on disease and its nature is experienced in different ways, from decreasing physical energy for caring for children, to physical separation and increasing disability, future hospitalization or impending death. Mothering could be disrupted even when women are physically present with their children .Women with breast cancer (BC) have expressed feelings such as guilt , being dThe concept of disrupted mothering was identified by Jackson who suggested that women experience guilt and distress when their mothering role is disrupted, and that this disruption may be had serious and long-term outcomes . DisruptIt is pertinent to note that in reviewing existing literature on the subject matter, disruption seems to be an incidental concept mentioned mainly in the titles or bodies of research articles, and not framed as a distinct concept in the literature. Focus upon mothering in the context of specific diseases is valuable, especially when trying to discern the overall effect of illness on mothering. It would be therefore valuable to examine the disruptive nature of illness in the context of mothering generally . HoweverSeveral methods for development and analysis of concepts are available. One of the most widely used methods in nursing is the McEwen and Wills’ Hybrid Model that refines concepts , 14, elidisrupted mothering/parenting, disrupting maternal /motherhood and breast cancer. As articles in the cancer/breast cancer setting were scanned, the search was broadened by using the main terms, ‘disrupted mothering’ and ‘care for children’. Reference lists of identified studies were reviewed to include all relevant studies (hand searching). Keywords included: “Mothering disruption”, “Disruption in mothering role”, “Disrupting Maternal” OR “Motherhood”; Breast cancer: "Breast Neoplasm" OR "Breast Tumors" OR "Malignant Neoplasm of Breast" OR "advanced breast cancer" OR "breast cancer recurrence". Article inclusion criteria was for relevant original articles and reviews articles which included the keywords in their title or abstract and papers with full text. We excluded non-English and non-Persian Language papers and papers discussing development of instrument (2 articles). Overall, 1850 abstracts were reviewed and eventually 27 studies , and title and abstract screening were undertaken by the first author to identify publications that did not meet the inclusion criteria. The first and second authors independently screened the full texts of the selected publications to match the eligibility criteria. The following data were extracted: author name, publication year, region, sample size, study methodology and key findings as antecedents, attributes and consequences of mothering disruption. For this purpose, the selected articles were read several times and independent of each other by all authors in order to extract appropriate codes, searching for words and phrases that related to disrupted mothering. Codes were reviewed, extracted into several categories such as antecedents, attributes and consequences of mothering disruption concept . The resA qualitative conventional content analysis approach was used to explore the experience of Iranian mothers with BC. Following ERB approval, participants were recruited using purposive sampling. The twenty participants eligible for the study were those who met the following inclusion criteria: had a confirmed diagnosis of BC, attended the oncology center of Shahid Ghazi Tabatabaei Hospital, had children 16 years and/or younger who were living with the participant and had deep and rich experiences about mothering during BC and its treatment. Participants were mostly aged 35–49 years, had completed a course of initial treatment for BC in the last one year and were also at the follow-up stage without any signs of recurrence. Methods to ensure the protection of human rights, including the voluntary nature of participation were discussed with participants and oral and written informed consent was obtained from them at the beginning of the interview. Data were collected by the primary researcher. Participants were interviewed at a place of their choice, with each interview audiotaped and lasting 35–80 min. The interview continued until data saturation.The interview guide developed for this study is provided as Additional file Finally, this analytical stage involved a comparison of findings from the field with findings that emerged during the theoretical phase (the existing literature) by the authors who sought to establish the relevance of findings to clinical practice.After reviewing the literature, the following definitions surfaced regarding the meaning of disrupted mothering. Disrupted mothering, has been defined as a woman perceiving that her maternal life has become disordered . LetteneIn the Table These include evolving self-identities from healthy mother to patient (23), and loss of role/sense of self and self-preservation (24). Mercer viewed maternal identity as the end point of the process of role attainment and articulated the stages of role attainment  during which maternal role behaviors evolve . In the The literature search revealed various concepts of the maternal role. Maternal role was defined as the behavioral responses to the expectations from a new mother and the mother’s perception of responsive mothering . In anotMaternal responsiveness is defined as promptness or frequency of response to the infant’s signals . HoweverMothers with BC are distressed by the times, when their illness, through hospitalization and treatment, fatigue or disability, prevents them from caring for their children as they normally would. The prognosis, treatment and nature of the diseases means that the disruption is experienced in different ways, from having less energy for caring for and playing with children, to physical separation and increasing disability, future hospitalization or impending death. Mothering could be disrupted even when women were physically present with their children .Critical event is a disruptive experience in the structure of everyday life, and this experience may be labelled as a form of biographical disruption. Biographical disruptions refer to the cessation of progress in the life of an individual by reason of critical illness . The conAccording to the analysis of the transcribed interview data, three main categories emerged for defining the mothering disruption concept. In the Table Mothers with BC perceived their health status differently than healthy mothers and expressed their doubts about the adequacy of care for their children due to their physical and mental (anxiety and depression) challenges, thus giving rise to a decline in the belief in good mothering ability. The authors perceive this to be a form of reduced maternal sensitivity. Reduced maternal sensitivity or maternal insensitivity is the inability of mothers to respond to behaviors arising from children's needs. Mothers reported that they sometimes felt incapable of caring their children as any ideal mother would, and the conflicting feelings of being able or unable to care for children made them physically and mentally exhausted the more. They also reported that in a bid to pursue rigorous and aggressive treatment regimens and to overcome fatigue of BC by having long rests, they became physically and emotionally detached from their relationship with their children and thus were unavailable to respond to their children's needs.Another concept that emerged from the interviews was an imbalance between roles as typified by the mothers’ accounts of juggling the role of self-care with child care. The mothers reported that in the course of the illness, they had disease-related needs that had to be met in order for them to be able to continue their maternal role and for their health to be restored to a reasonable quality. Many reported being faced with issues like fatigue, disability, and motor limitations, added to the need to complete their treatment regimen. This often clashed with the expectations of the society in which they found themselves. Some mothers in this study admitted to trying to prioritize their children’s needs with regards to maternal duties, but physical disabilities and symptoms of the disease often made it difficult for them to coordinate self-care and child-care activities. Others complained of being emotionally impaired from being employed and having multiple roles at the same time, such as attending to spousal need, motherhood and illness, thus making the role of mother tedious and less attractive.In discussing maternal role failure, inefficiency in executing maternal roles was cited by many as a cause of role failure by some mothers. Many of the mothers reported being burdened by numerous duties which included education and protection of children in a background of illness and unpleasant treatment complications, the latter often making it difficult for such mothers to have regular access to their children. Thus, a reduction in the mothers’ interactions with their children led to poor quality of care for child. Consequently, mothers were seen by family members and neighbors alike as having failed to meet expectations of maternal role, in terms of education, socialization, and protection as a good model of motherhood .After analyzing all aspects of the concept using a hybrid model and based on all the two phases discussed above, The authors classified the findings of the previous two stages into three categories to explain the integrated definition of mothering disruption, which included (1) disease as threating maternal role and identity, (2) inability to interpret and respond to child behavior, and (3) support for transitioning from being patient toward maternal competency.Authors arrived at the following conclusions about the opinions of this cohort of Iranian mothers with BC regarding disrupted mothering. In their opinion, the overbearing and difficult situation they faced arising from the illness and its treatment combined with the continuation of the mothering role threatened their maternal role and identity. Also grossly affected was their ability to interpret and respond to their children’s behaviors and needs, especially the dependent ones, even when they tried to ignore the burden of the illness and ‘being a patient’ and just carry out their mothering role. Thus, mothers need the help of people around them for support as they transition from being sick to recovering and being able to playing theirs roles as mothers Table .Table 3TMothers with BC struggle with physical, mental, and social challenges after diagnosis and cancer treatment and this negatively impacts on their family life as many are unable to fulfil their mothering role subsequently  as they One aspect of the life of the woman with BC, which is her self-identity, is often under assault as a result of the disease and its treatment. Strickland has suggested following the cancer diagnosis, the mother finds herself unintentionally in a very difficult situation where she tries hard to be both a good patient and a dedicated mother . The thrThe second construct in this concept analysis was “the inability of mothers to interpret and respond to their children's behaviors and needs. The cancer diagnosis is known to affect patients’ psychology as well as their confidence in carrying out their parenting role . It has Many of the women felt they were not recognized as mothers, but instead were treated as ‘just a patient’ and had a lot of troubles fulfilling their responsibilities regarding the well-being of children and the stability of family life. This is the bane of the third construct of analysis which was “support for transitioning from being patient toward maternal competency.” This narrative affirms previous findings that point to the need for a strong support structure for women with BC during the entire disease and treatment continuum and beyond and nurses can address their concerns. Previous evidence suggests that the usual services provided in health centers do not fit the needs of mothers, as the diagnosis of cancer can be very destructive and complex, given the unique position of women in playing their role as mothers . This isAlthough this study possesses many strengths, it is not without limitation. This study was limited to patients who received follow-up at a single hospital. Therefore, their experiences might not be generalizable to the general population of Iranian mothers with BC. However, the authors consider that it will be relevant locally in Tabriz and similar regions of Iran.In sum, this study is significant in that it is the first time a study has proposed a conceptual definition of the mothering disruption of these mothers in Iran. It reveals that Iranian women with BC express the same fears and concerns regarding the disruption of their mothering roles and identities, as other mothers with BC globally. The definitions, attributes, antecedents, consequences, and integrated definition of mothering disruption identified in the present study can be used to evaluate mothering disruption in healthcare settings and develop theory-based interventions for decreasing this disruption in mothers with BC. This concept analysis provides information, which can be used in nursing practice, education, research, and management.By analyzing the concept of disrupted mothering as conducted in this study, through the integration of narratives provided by the women with BC with the evidence from scientific literature, an opportunity has been created for healthcare providers in caring for Iranian women with BC to have a better understanding of the experiences of their patients in order to tailor the care and support these women receive to enable them retain their mothering identities, fulfil their mothering roles and still judiciously comply with all treatment decisions raised during their care in hospital and in the post-hospitalization period. While this study has attempted to fill the gaps in literature concerning disrupted mothering in the context of women in an Islamic culture, it also facilitates clinical and transferable knowledge in nursing performance and it can help nurses and other clinicians choose the appropriate interventions to help these mothers find a balance between self-care and other mothering roles.Future research directions would include specific culturally-sensitive psychosocial interventions targeted at eliminating the disruptions in mothering and the development of tools to measure the level of disruption in mothering, by the healthcare providers to aid in early identification and prompt resolution of disruptions in the mothering role and identity. In addition, as the definition of disrupted mothering is likely to vary across treatment stages, further comparative research is needed to analyze the concept of mothering disruption in the early and late stages of breast cancer disease and treatment continuum.Additional file 1. The PRISMA Checklist for study.Additional file 2. The COREQ Checklist for study.Additional file 3. The interview guide was developed for the study.


Schizosaccharomyces pombe critically depends on the connection between the lipid membrane and F-actin. The fission yeast endocytic protein End4 (homologous to Sla2 in budding yeast and HIP1R in human) contains a N-terminal domain that binds to PIP2 on the membrane, and a C-terminal THATCH domain that is postulated to be a binding partner of F-actin in vivo. Purified THATCH domain of the budding yeast Sla2, however, shows low affinity to F-actin in vitro. We tested if isolated THATCH domain still has low affinity to F-actin in vivo, using TEV protease (TEVp)-mediated protein cleaving to separate the THATCH domain from the rest of End4. Our results indicate that the isolated THATCH domain of End4 is unable to bind F-actin independently in vivo, consistent with the low affinity of the THATCH domain to F-actin measured from in vitro binding assays.Clathrin mediated endocytosis (CME) in the fission yeast  The N-terminus of End4 binds to PIP2 on the membrane together with Ent1p, and the C-terminus of End4 shares sequence similarities to the actin binding domain of talin, and is therefore named THATCH  . The crystal structures of THATCH domains from HIP1R and talin are five-helix-bundles . The THATCH domain of Sla2 is critical for linking F-actin to the endocytic coat during CME in budding yeast . The affinity of purified THATCH domains for actin filaments has been measured in vitro by multiple groups . Although structurally similar, the THATCH domain from HIP1R has the lowest affinity to actin among all tested THATCH domains, in some cases not significantly higher than that of the negative control with purified GST . This discrepancy in the actin-binding ability of the THATCH domain from in vitro and in vivo data could be explained by cryptic actin-binding sites that are activated in vivo, by a) post-translational modifications, b) the binding of other molecules, or c) force transmitted through the rest of the End4 molecule. All three binding site activation mechanisms have been found on talin, the molecule responsible for connecting the membrane to F-actin during cell adhesion through its 13 rod domains including the THATCH domain . A clear way to distinguish mechanism c) from a) and b) is through in vivo protein cleaving. By isolating the THATCH domain of End4 from the rest of End4 in the cytoplasm of the fission yeast, the native environment for possible post-translational modifications or binding partners of THATCH are preserved, but force transmission to the THATCH domain is prevented. Consequently, the cellular localization of the isolated THATCH domain is indicative of its direct affinity to F-actin in vivo.End4 is an endocytic protein that mediates the connection between the lipid membrane and the actin cytoskeleton in fission yeast . TEVp has been shown to work in diverse situations both in vivo and in vitro . The coding sequence of TEVp was integrated into the genome of fission yeast by CRISPR/Cas9(Fernandez and Berro 2016), and put under the control of the inducible promoter nmt1 (Forsburg 1993). We first verified that our approach for in vivo protein cleaving worked and did not have undesirable effects, by using TEVp to separate the mEGFP tag from a control protein. We used the Acp1 subunit of the canonical actin filament capping protein, which localizes to endocytic sites  and has comparable cytoplasmic concentration to End4 in the fission yeast . When Acp1 was tagged either with a regular linker or the TEVp recognition peptide, the majority of the mEGFP signal was detected at endocytic patches, which were enriched at the poles and the division plane of the fission yeast cells . These endocytic patches contained a large amount of F-actin. When the expression of TEVp was induced, we saw a drastic decrease of mEGFP signal from endocytic patches, suggesting the removal of the mEGFP tag from Acp1 molecules . As expected, the cleavage of TEVp demonstrated good specificity, and a point mutation in the TEVp recognition peptide prevented protein cleaving .We chose to use TEVp to perform in vivo, similarly to what was shown in vitro. In addition, our results demonstrate that the connection between the THATCH domain and the rest of the End4 molecule is necessary for its binding to actin filaments. We speculate that force transmission through the whole End4 protein is probably involved in exposing the cryptic F-actin binding sites.We then inserted the TEVp recognition peptide prior to the THATCH domain of End4. In wild-type cells, End4 localizes to endocytic patches in a pattern similar to Acp1 . The insertion of the TEVp recognition peptide did not change the localization of End4 when TEVp was not expressed . When TEVp was expressed, however, the THATCH domain was no longer found at endocytic patches but became diffusive in the cytoplasm and the nucleus, while the N-terminal fragment of End4 still showed polarized localization . Failure of the isolated THACTH domain to localize to endocytic patches demonstrates that the affinity of the THATCH domain to F-actin is low Yeast strains and mediaS. pombe strains used in this study were made though CRISPR/Cas9 mediated genome editing as reported in (Fernandez and Berro 2016), and the edited gene sequences were confirmed by colony PCR and sequencing. The coding sequence of TEVp was inserted into the low complex region 0.5kb upstream of pil1 locus  , under the control of the full strength nmt1 promoter (Forsburg 1993). S. pombe cells were cultured in YE5S , and imaged in EMM5S  after washing with EMM5S. Yeast cells were cultured at 32 °C with 200rpm shaking overnight to reach OD595nm reading between 0.3 and 0.5. The expression of TEVp was inhibited when yeast cells were cultured in YE5S media. The expression of TEVp was induced by transferring yeast cells into EMM5S media after multiple washes, and cells were imaged after overnight culture in EMM5S to allow for enough time for TEVp mediated protein cleavage.The Microscopyet al. 2012). All Acp1 strains were imaged and displayed with the same settings. For End4 strains, the mEGFP channel was imaged and displayed with the same settings, and the mScarlet-I channel was imaged and displayed with the same settings.Cells were imaged at room temperature on gelatin pads (25%) on glass slides. Samples were mounted on a Nikon TiE inverted microscope  with a CSU-W1 Confocal Scanning Unit  with a CFI Plan Apo 100X/1.45NA Phase objective . Images were captured with an iXon Ultra888 EMCCD camera . mEGFP tagged strains were excited with a 488-nm argon-ion laser and filtered with a single band pass filter 510/25. mScarlet-I tagged strains were excited with a 561-nm argon-ion laser and filtered with a single band pass filter 575/25. Fluorescent signals from the whole cell were collected by taking 21 optical sections each with 0.5µm thickness, and 2D maximum projected images were created for each strain by the Fiji distribution of ImageJ (Schindelin


Multiferroic nanostructures have been attracting tremendous attention over the past decade, due to their rich cross-coupling effects and prospective electronic applications. In particular, the emergence of some exotic phenomena in size-confined multiferroic systems, including topological domain states such as vortices, center domains, and skyrmion bubble domains, has opened a new avenue to a number of intriguing physical properties and functionalities, and thus underpins a wide range of applications in future nanoelectronic devices. It is also highly appreciated that nano-domain engineering provides a pathway to control the magnetoelectric properties, which is promising for future energy-efficient spintronic devices. In recent years, this field, still in its infancy, has witnessed a rapid development and a number of challenges too. In this article, we shall review the recent advances in the emergent domain-related exotic phenomena in multiferroic nanostructures. Specific attention is paid to the topological domain structures and related novel physical behaviors as well as the electric-field-driven magnetic switching via domain engineering. This review will end with a discussion of future challenges and potential directions. Due to the substantial size and surface effects, the domain structures in these multiferroic components can be greatly changed, and classical domain patterns may be replaced by some unique complex domain structures . T. T95]. TFinally, we present a brief discussion of an emergent effect observed in 0–0 type heterostructured nanoislands in which domain engineering may also be utilized to tune the EDMS behavior. It is noted that distinctly different polarization switching behaviors will be expected once a ferroelectric film is patterned into small nanoislands, due to the release of clamping effects from the substrate and surrounding domains. For instance, it was found that a perpendicular electric field drives the BFO thin film to undergo a ferroelastic 109° polarization switching, followed by a relaxation to the 180° direction. This observation does not work for small BFO nanoislands where only a single ferroelastic switching occurs ,101. TheMultiferroic nanostructures possess a wealth of exotic domain structures, in particular rich topological states  have enabled the observation of polar domains at atomic or nanometer scales ,28, whilin situ the domain structure and its dynamics against various stimuli. It is also particularly challenging for probing nanoscopic and multi-functional cross-coupling behaviors.mapping of vortices in ferroelectric nanoparticles was obtained using the X-ray-based Bragg coherent diffractive imaging technique . Howeverin situ monitoring of domain structure and its dynamics, but also probing its related functional response at the nanoscale, including domain wall conductivity, memrestive, photovoltaics, and ME response etc. Furthermore, it is expected that tip-enhanced (or near-field) optical probing in Raman, electro-optic, and MOKE modes can also be incorporated in the SPM system. Certainly, spatial and temporal resolution should be given the top priority for all these advanced probing functionalities.Nevertheless, it is worth spending some time on the multi-functional SPM technique as a versatile and powerful nanoscale probe of multi-functionalities. Nowadays, multi-field stimuli, like electric field, magnetic field, light illumination, strain field, and thermal field, are able to be integrated with the advanced SPM technique. Figure Although there are still limited examples demonstrating the potential applications of these topological states, the intriguing properties that have been revealed are sufficient for us to posit some possible devices. High-density memory (or logic) devices could be one application terminal for the topological domains , offering high density, fast switching, and energy-efficient read/writing. Along this line, deterministic control of the topological domains and enhanced switching performances  is needed. In addition, accurate and efficient readout of different states can be a critical issue, whereby non-destructive readout is highly appreciated . Other cAnother issue is the integration of material structures with current semiconductor technologies, and the isolated nanoislands may show some advantages over the crossbar architectures. Polar skyrmions could be applied in track record memory, while capabilities to inject and drive the skyrmions are needed. Other prospective applications, like transistors based on negative capacitors, strain/magnetic/optical sensors, and microwave devices based on domain resonance, can also be expected.Last but not least, it should be pointed out that most of the results reviewed in this article were obtained based on TEM and SPM observations, and this leaves a gap between the microscopic findings and practical device applications. Bridging this gap requires further efforts.