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Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD- GRN ) or C9orf72 (FTD- C9orf72 ) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD- GRN cases, FTD- C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD- GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD- C9orf7 2. FTD- GRN was distinguished from FTD- C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD- GRN and FTD- C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD- GRN . We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD- GRN . Since FTD- GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.

The number, position, and configuration of double bonds in lipids affect membrane fluidity and the recruitment of signaling proteins. Studies on mammalian sphingolipids have focused on those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Using high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS), we observed a marked accumulation of lipids containing a di-unsaturated sphingadiene base in the hippocampus of mice lacking the metabolic enzyme sphingosine kinase 2 (SphK2). The double bonds were localized to positions C4–C5 and C14–C15 of sphingadiene using ultraviolet photodissociation-tandem mass spectrometry (UVPD-MS/MS). Phosphorylation of sphingoid bases by sphingosine kinase 1 (SphK1) or SphK2 forms the penultimate step in the lysosomal catabolism of all sphingolipids. Both SphK1 and SphK2 phosphorylated sphinga-4,14-diene as efficiently as sphingosine, however deuterated tracer experiments in an oligodendrocyte cell line demonstrated that ceramides with a sphingosine base are more rapidly metabolized than those with a sphingadiene base. Since SphK2 is the dominant sphingosine kinase in brain, we propose that the accumulation of sphingadiene-based lipids in SphK2-deficient brains results from the slower catabolism of these lipids, combined with a bottleneck in the catabolic pathway created by the absence of SphK2. We have therefore uncovered a previously unappreciated role for SphK2 in lipid quality control.

Blockchain technology is currently recognized as the most potential new key technology, it can bring earth shaking changes, it is expected to trigger a new round of technological innovation and industrial change, and cause market attention. The purpose of this paper is to study the security of digital financial transactions based on blockchain technology. Firstly, the security of sdte is analyzed, and the DoS attacks that each role may launch, the attacks that a single role may send, and the attacks that can be launched by multiple roles in collusion are analyzed. It shows that sdte can resist these attacks and has strong security. Then, the related environment of the system test is described. Then, the performance test and analysis are carried out from the key security transmission, the execution of smart contract in the trusted environment SGX and the total running time. The experimental results show that the extra time consumed by using the k-nearest neighbor (KNN) algorithm to process data is less than 0.45s, At the same time, the additional cost brought by the system is also acceptable.

With the rapid iterative development of computer information technology, financial technology is also constantly innovating. In this context, the digital currency which should be used in blockchain technology has been developed and popularized rapidly. However, effective supervision of digital currency has become a big problem in the rapid development of blockchain and digital currency. Based on this, this paper first studies the blockchain technology and application, analyzes the technology principle and application of blockchain, secondly, analyzes the digital currency supervision model based on blockchain technology, and studies the necessity of the construction of the supervision system and the strategy of supervision.

PurposeThis paper aims to the perspective of stakeholders, from external variables of the Building Information Modeling (BIM) system, users, task flow, the nature of the development of the execution process, organizational structure and policy impacts, that established a relationship among the internal concepts and intentions for the BIM application, individual or organizational differences, controlling interference factors and environmental constraints, discussed the combination of the values and barriers of BIM implementation.Design/methodology/approachThrough the co-occurrence statistics and genre analysis based on co-citation context analysis and constructs the common information that impacts the combination of values and barriers of BIM implementation. Then, the paper chose the expert database of the green construction and intelligent building branch of the China construction association, and obtained 104 sample data through modified snowball sampling, using exploratory factor analysis with factor load linear functions, combined factor variance contribution rate weights.actor variance contribution rate weights.FindingsThe results show that eight aspects can be defined as the values of BIM implementation (VI), and the barriers of BIM implementation (BI) mainly come from five aspects caused by insufficient cognition and two aspects of an uncertain value in China.Originality/valueThis research reflects a combined evaluation of the values of BIM implementation and barriers of BIM and highlights the significance of the sustainable development of BIM technology and the value of building future informatization applications.

Myelin turnover is essential for its structural and functional integrity, yet how this particularly lipid-rich membrane is renewed and why it deteriorates with ageing remain unresolved. Combining deuterium oxide administration in mice with high resolution lipidomics, we establish that brain lipid turnover rates are highly heterogeneous, differ by brain region, and depend primarily on lipid class. Half-lives of common glycerophospholipids in purified myelin were under 2 months whereas many sphingolipids exhibited half-lives exceeding 8 months, dependent on acyl chain length and saturation. Myelin sphingolipid and cholesterol replacement rates in the corpus callosum decreased markedly between 3 and 12 months of age, while disrupting lipid trafficking through ApoE ablation preferentially impaired cholesterol turnover and incorporation into myelin. Our results establish that myelin renewal occurs through continual replacement of individual lipid constituents in a manner that depends on lipid class, hydrophobicity, and ApoE-dependent trafficking, and that this process slows significantly with ageing.Competing Interest StatementThe authors have declared no competing interest.Footnotes* No changes, except for labelling of the supplemental files (link namings were incorrect from automatic labelling from biorxiv. The files themselves are identical to previous upload).Funder Information DeclaredNational Health and Medical Research Council of Australia, 2028164, 2002660Australian Research Council Future Fellowship, FT190100082

Therapeutics that promote oligodendrocyte survival and remyelination are needed to restore neurological function in demyelinating diseases. Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through five G-protein coupled receptors. S1P receptor agonists such as Fingolimod are valuable immunosuppressants used to treat multiple sclerosis, and promote oligodendrocyte survival. However, the role for endogenous S1P, synthesized by the enzyme sphingosine kinase 2 (SphK2), in oligodendrocyte survival and myelination has not been established. This study investigated the requirement for SphK2 in oligodendrocyte survival and remyelination using the cuprizone mouse model of acute demyelination, followed by spontaneous remyelination. Oligodendrocyte density did not differ between untreated wild-type (WT) and SphK2 knockout (SphK2-/-) mice. However, cuprizone treatment caused significantly greater loss of mature oligodendrocytes in SphK2-/- compared to WT mice. Following cuprizone withdrawal, spontaneous remyelination occurred in WT but not SphK2-/- mice, even though progenitor and mature oligodendrocyte density increased in both genotypes. Levels of cytotoxic sphingosine and ceramide were higher in the corpus callosum of SphK2-/- mice, and in contrast to WT mice, did not decline following cuprizone withdrawal in SphK2-/- mice. We also observed a significant reduction in myelin thickness with ageing in SphK2-/- compared to WT mice. These results provide the first evidence that SphK2, the dominant enzyme catalysing S1P synthesis in the adult brain, is essential for remyelination following a demyelinating insult and myelin maintenance with ageing. We propose that persistently high levels of sphingosine and ceramide, a direct consequence of SphK2 deficiency, may block remyelination. Competing Interest Statement The authors have declared no competing interest.

The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability and function. GalCer and ST are synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement for C22-C24 sphingolipid synthesis in myelin lipid biosynthesis and stability, we generated mice lacking CerS2 specifically in myelinating cells (CerS2ΔO/ΔO). At 6 weeks of age, normal-appearing myelin had formed in CerS2ΔO/ΔO mice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2ΔO/ΔO mice was compensated by greatly increased levels of C18 sphingolipids. A distinct microglial population expressing high levels of activation and phagocytic markers such as CD64, CD11c, MHC class II, and CD68 was apparent at 6 weeks of age in CerS2ΔO/ΔO mice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2ΔO/ΔO mice. By 16 weeks, CerS2ΔO/ΔO mice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2ΔO/ΔO mice died between 16 and 26 weeks of age. This study highlights the importance of sphingolipid acyl chain length for the structural integrity of myelin, demonstrating how a modest reduction in lipid chain length causes exposure of a denatured myelin protein epitope and expansion of phagocytic microglia, followed by axon pathology, myelin degeneration, and motor deficits. Understanding the molecular trigger for microglial activation should aid the development of therapeutics for demyelinating and neurodegenerative diseases. Oligodendrocytes lacking CerS2 produce myelin using sphingolipids with C16/C18 instead of C22/C24 N-acyl chains C22/C24 myelin sphingolipids are essential for myelin stability, microglial quiescence, and survival beyond young adulthood

The number, position, and configuration of double bonds in lipid acyl chains affects membrane packing, fluidity, and recruitment of signalling proteins. Studies on mammalian sphingolipids have focused on those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Sphingolipids with a di-unsaturated sphingadiene base have been reported but are poorly characterised. Employing high-resolution untargeted mass spectrometry, we observed marked accumulation of lipids containing a sphingadiene base, but not those with a more common sphingosine backbone, in the hippocampus of mice lacking the metabolic enzyme sphingosine kinase 2 (SphK2). Applying ultraviolet photodissociation tandem mass spectrometry (UVPD-MS/MS) the double bonds were confidently assigned to the C4-C5 and C14-C15 positions of the sphingoid base. Sphingosine kinases are involved in lysosomal catabolism of all sphingolipids, producing sphingoid base phosphates that are irreversibly degraded by sphingosine 1-phosphate lyase. Both SphK1 and SphK2 phosphorylated sphinga-4,14-diene as efficiently as sphingosine, however deuterated tracer experiments demonstrated that ceramides with a sphingosine base are more rapidly metabolised in cultured cells than those with a sphingadiene base. SphK2 silencing significantly impeded the catabolism of both sphingosine- and sphingadiene-based sphingolipids. Since SphK2 is the dominant sphingosine kinase in brain, we propose that accumulation of sphingadiene lipids in SphK2-deficient brains results from the intrinsically slower catabolism of sphingadiene lipids, combined with a bottleneck in the catabolic pathway created by the absence of SphK2. We speculate that accumulation of these lipids in the absence of SphK2 function may affect the fluidity and signalling properties of cell membranes.

Objective To investigate the effects of Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH) on social functioning in individuals with autism spectrum disorders (ASD). Methods Relevant studies on TEACCH intervention in ASD individuals were systematically searched in PubMed, The Cochrane Library, Embase, CNKI, and Wanfang from inception to March 2024. The main outcome measures were social, cognitive performance, fine motor, communication, daily living, imitation, and cognitive verbal skills. Data were meta-analyzed using R studio (4.1.2). Results Eleven studies involving 701 ASD individuals were included in this study. The TEACCH group had significantly higher socialization score [MD = 0.6, 95% CI(0.2, 1.0)], Cognitive Performance Scale score [MD = 1.34, 95% CI(0.09, 2.58)], and fine motor score [MD = 0.7, 95% CI(0.4, 1.0)] but significantly lower Autism Behavior Checklist score [MD = -1.57, 95% CI(-2.11, -1.02)], Childhood Autism Rating Scale score [MD= -0.7, 95%CI(-1.0, -0.3)], and Autism Treatment Evaluation Checklist score [MD= -0.7, 95% CI(-1.0, -0.3)] compared to the control group. There were no significant differences in other outcome measures. Conclusion TEACCH is a promising intervention for improving the social skills, cognitive performance, and fine motor functions of ASD individuals. However, further studies are warranted to confirm the effectiveness of TEACCH on ASD core symptoms.