ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies

Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker-Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of Walker-Warburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker-Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy

Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan

Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG. © 2013 The American Society of Human Genetics.Funding for UK10K was provided by the Wellcome Trust under award WT091310

Environmental and technical evaluation of cement reduction and test methods for fibre reinforced shotcrete in tunnels

The dominating support method for hard rock tunnels today is use of fibre reinforcedshotcrete in combination with rock bolts. The fibre reinforced shotcretesecures smaller blocks, while rock bolts are used to support larger blocks in therock. Application of shotcrete is done by spraying against the rock surface usingcompressed air. The use of accelerators result in fast strength developmentand adhesive properties, which are two characteristics of great importance whenconstructing tunnels.This thesis aims at increasing the understanding of climate impact from fibre reinforcedshotcrete in tunnel construction. The focus is on reducing the climateimpact with two methods: reducing the share of cement in the shotcrete mixturethrough substitution with addition materials and using better test methods for fibres.Cement is one of the most important ingredients in concrete, however alsothe largest contributor to CO2 emissions. Reducing the cement amount is thereforea way of reducing the emissions of concrete. In addition, when testing the performanceof fibres, different methods can lead to a spread in the results, causing anoveruse of fibres in the shotcrete.First, the thesis investigated the use of alternative binder materials, especiallyGround Granulated Blast Furnace Slag (GGBS), as a substitute for cement. Experimentaltesting was performed in a laboratory to evaluate the compressive strengthfor shotcrete with different amounts of GGBS. Testing was performed after one andseven days in order to evaluate the early strength. Second, the thesis investigatedthe use of fibre reinforcement and the possibilities of reducing the fibre dosagewhen changing fibre type and test method. Numerical modelling was performedfor two test methods, beam and panel testing, based on experimental data. Thethesis evaluated the environmental performance in terms of Global Warming Potentialfor both fibres and binder.The results show that substituting cement with GGBS has the largest potential tolower the CO2 emissions from fibre reinforced shotcrete. In addition, the fibredosage can be lowered by changing fibre type, but also test method. Also thislowers the emissions, however the main emissions origins from the binder part

Environmental and technical evaluation of cement reduction and test methods for fibre reinforced shotcrete in tunnels

The dominating support method for hard rock tunnels today is use of fibre reinforced shotcrete in combination with rock bolts. The fibre reinforced shotcrete secures smaller blocks, while rock bolts are used to support larger blocks in the rock. Application of shotcrete is done by spraying against the rock surface using compressed air. The use of accelerators result in fast strength development and adhesive properties, which are two characteristics of great importance when constructing tunnels. This thesis aims at increasing the understanding of climate impact from fibre reinforced shotcrete in tunnel construction. The focus is on reducing the climate impact with two methods: reducing the share of cement in the shotcrete mixture through substitution with addition materials and using better test methods for fibres. Cement is one of the most important ingredients in concrete, however also the largest contributor to CO2 emissions. Reducing the cement amount is therefore a way of reducing the emissions of concrete. In addition, when testing the performance of fibres, different methods can lead to a spread in the results, causing an overuse of fibres in the shotcrete. First, the thesis investigated the use of alternative binder materials, especially Ground Granulated Blast Furnace Slag (GGBS), as a substitute for cement. Experimental testing was performed in a laboratory to evaluate the compressive strength for shotcrete with different amounts of GGBS. Testing was performed after one and seven days in order to evaluate the early strength. Second, the thesis investigated the use of fibre reinforcement and the possibilities of reducing the fibre dosage when changing fibre type and test method. Numerical modelling was performed for two test methods, beam and panel testing, based on experimental data. The thesis evaluated the environmental performance in terms of Global Warming Potential for both fibres and binder. The results show that substituting cement with GGBS has the largest potential to lower the CO2 emissions from fibre reinforced shotcrete. In addition, the fibre dosage can be lowered by changing fibre type, but also test method. Also this lowers the emissions, however the main emissions origins from the binder part.Den dominerande förstärkningsmetoden för tunnlar i hårt berg idag är fiberarmerad sprutbetong i kombination med bergbultar. Den fiberarmerade sprutbetongen säkrar mindre block, medan bergbultar säkrar större block från att falla ner. Sprutbetongen appliceras genom sprutning direkt mot bergytan men hjälp av tryckluft. Användning av acceleratorer medför snabb hållfasthetsutveckling och vidhäftande egenskaper, vilka är av stor vikt vid tunnelkonstruktion. Syftet med examensarbetet är att öka förståelsen för klimatpåverkan från fiberarmerad sprutbetong i tunnelkonstruktion. Fokus är att undersöka minskningar i klimatpåverkan med två metoder: minska andelen cement i betongblandningen genom ersättning med alternativa material och använda bättre testmetoder för fibrer. Cement är en av de viktigaste ingredienserna i betong, men också den största bidragande faktorn till koldioxidutsläpp. Minskning av andelen cement är därför ett sätt att reducera utsläppen från betong. Dessutom kan valet av testmetod ha stor påverkan på vilken dosering av fibrer som krävs. Examensarbetet undersökte först användningen av alternativa bindemedelsmaterial, speciellt granulerad masugnsslagg, i sprutbetong som ett ersättningsmaterial till cement. Experiment i labb utfördes för att utvärdera tryckhållfastheten för gjuten sprutbetong med olika andelar granulerad masugnsslagg. Testning genomfördes efter en respektive sju dagar för att utvärdera hur slagg påverkar den tidiga hållfastheten. Användningen av fiberarmering och möjligheten att reducera fiberinnehållet vid byte av fibersort och testmetod undersöktes sedan. Numerisk modellering genomfördes för två testmetoder, balk- och plattest, baserat på experimentell data. Examensarbetet utvärderade klimatpåverkan i termer av Global Warming Potential, GWP, för både fibrer och bindemedel i sprutbetong. Resultaten visar att ersättning av cement med granulerad masugnsslagg har den största potentialen att minska koldioxidutsläppen från fiberarmerad sprutbetong. Dessutom kan fiberdoseringen minskas genom ändrad fibertyp samt ändrad testmetod, vilket också minskar utsläppen. Emellertid härstammar de största utsläppen från bindemedlet

Environmental and technical evaluation of cement reduction and test methods for fibre reinforced shotcrete in tunnels

The dominating support method for hard rock tunnels today is use of fibre reinforcedshotcrete in combination with rock bolts. The fibre reinforced shotcretesecures smaller blocks, while rock bolts are used to support larger blocks in therock. Application of shotcrete is done by spraying against the rock surface usingcompressed air. The use of accelerators result in fast strength developmentand adhesive properties, which are two characteristics of great importance whenconstructing tunnels.This thesis aims at increasing the understanding of climate impact from fibre reinforcedshotcrete in tunnel construction. The focus is on reducing the climateimpact with two methods: reducing the share of cement in the shotcrete mixturethrough substitution with addition materials and using better test methods for fibres.Cement is one of the most important ingredients in concrete, however alsothe largest contributor to CO2 emissions. Reducing the cement amount is thereforea way of reducing the emissions of concrete. In addition, when testing the performanceof fibres, different methods can lead to a spread in the results, causing anoveruse of fibres in the shotcrete.First, the thesis investigated the use of alternative binder materials, especiallyGround Granulated Blast Furnace Slag (GGBS), as a substitute for cement. Experimentaltesting was performed in a laboratory to evaluate the compressive strengthfor shotcrete with different amounts of GGBS. Testing was performed after one andseven days in order to evaluate the early strength. Second, the thesis investigatedthe use of fibre reinforcement and the possibilities of reducing the fibre dosagewhen changing fibre type and test method. Numerical modelling was performedfor two test methods, beam and panel testing, based on experimental data. Thethesis evaluated the environmental performance in terms of Global Warming Potentialfor both fibres and binder.The results show that substituting cement with GGBS has the largest potential tolower the CO2 emissions from fibre reinforced shotcrete. In addition, the fibredosage can be lowered by changing fibre type, but also test method. Also thislowers the emissions, however the main emissions origins from the binder part

Environmental and technical evaluation of cement reduction and test methods for fibre reinforced shotcrete in tunnels

The dominating support method for hard rock tunnels today is use of fibre reinforced shotcrete in combination with rock bolts. The fibre reinforced shotcrete secures smaller blocks, while rock bolts are used to support larger blocks in the rock. Application of shotcrete is done by spraying against the rock surface using compressed air. The use of accelerators result in fast strength development and adhesive properties, which are two characteristics of great importance when constructing tunnels. This thesis aims at increasing the understanding of climate impact from fibre reinforced shotcrete in tunnel construction. The focus is on reducing the climate impact with two methods: reducing the share of cement in the shotcrete mixture through substitution with addition materials and using better test methods for fibres. Cement is one of the most important ingredients in concrete, however also the largest contributor to CO2 emissions. Reducing the cement amount is therefore a way of reducing the emissions of concrete. In addition, when testing the performance of fibres, different methods can lead to a spread in the results, causing an overuse of fibres in the shotcrete. First, the thesis investigated the use of alternative binder materials, especially Ground Granulated Blast Furnace Slag (GGBS), as a substitute for cement. Experimental testing was performed in a laboratory to evaluate the compressive strength for shotcrete with different amounts of GGBS. Testing was performed after one and seven days in order to evaluate the early strength. Second, the thesis investigated the use of fibre reinforcement and the possibilities of reducing the fibre dosage when changing fibre type and test method. Numerical modelling was performed for two test methods, beam and panel testing, based on experimental data. The thesis evaluated the environmental performance in terms of Global Warming Potential for both fibres and binder. The results show that substituting cement with GGBS has the largest potential to lower the CO2 emissions from fibre reinforced shotcrete. In addition, the fibre dosage can be lowered by changing fibre type, but also test method. Also this lowers the emissions, however the main emissions origins from the binder part.Den dominerande förstärkningsmetoden för tunnlar i hårt berg idag är fiberarmerad sprutbetong i kombination med bergbultar. Den fiberarmerade sprutbetongen säkrar mindre block, medan bergbultar säkrar större block från att falla ner. Sprutbetongen appliceras genom sprutning direkt mot bergytan men hjälp av tryckluft. Användning av acceleratorer medför snabb hållfasthetsutveckling och vidhäftande egenskaper, vilka är av stor vikt vid tunnelkonstruktion. Syftet med examensarbetet är att öka förståelsen för klimatpåverkan från fiberarmerad sprutbetong i tunnelkonstruktion. Fokus är att undersöka minskningar i klimatpåverkan med två metoder: minska andelen cement i betongblandningen genom ersättning med alternativa material och använda bättre testmetoder för fibrer. Cement är en av de viktigaste ingredienserna i betong, men också den största bidragande faktorn till koldioxidutsläpp. Minskning av andelen cement är därför ett sätt att reducera utsläppen från betong. Dessutom kan valet av testmetod ha stor påverkan på vilken dosering av fibrer som krävs. Examensarbetet undersökte först användningen av alternativa bindemedelsmaterial, speciellt granulerad masugnsslagg, i sprutbetong som ett ersättningsmaterial till cement. Experiment i labb utfördes för att utvärdera tryckhållfastheten för gjuten sprutbetong med olika andelar granulerad masugnsslagg. Testning genomfördes efter en respektive sju dagar för att utvärdera hur slagg påverkar den tidiga hållfastheten. Användningen av fiberarmering och möjligheten att reducera fiberinnehållet vid byte av fibersort och testmetod undersöktes sedan. Numerisk modellering genomfördes för två testmetoder, balk- och plattest, baserat på experimentell data. Examensarbetet utvärderade klimatpåverkan i termer av Global Warming Potential, GWP, för både fibrer och bindemedel i sprutbetong. Resultaten visar att ersättning av cement med granulerad masugnsslagg har den största potentialen att minska koldioxidutsläppen från fiberarmerad sprutbetong. Dessutom kan fiberdoseringen minskas genom ändrad fibertyp samt ändrad testmetod, vilket också minskar utsläppen. Emellertid härstammar de största utsläppen från bindemedlet

Post-Cracking Behaviour of Fibre-Reinforced Shotcrete: A Numerical Comparison between Beams and Panels

Fibre-reinforced shotcrete is an essential part of the support of hard rock tunnels. Due to the complexity of the design, a combination of empirical and numerical analysis is commonly used in the design. The required dosage of fibres for structural purposes is determined based on minimum energy absorption or residual flexural strength. The latter is derived from tests on beams, while energy absorption is tested on panels. It is widely known that tests on beams suffer from a large scatter in results due to the short fracture zone in combination with the natural variation in the number and orientation of fibres which bridge the crack. This impacts the characteristic strength derived from these tests negatively. This paper presents a numerical study to investigate how the test method affects the required dosage of fibres. First, a non-linear model for shotcrete based on continuum damage mechanics is presented. Thereafter, the model is tuned against test results for beams and panels. A model tuned on beams is then used to simulate the response of a panel and vice versa. The results indicate that the size of the fracture zone has a significant effect on the post-cracking behaviour and that the required dosage of fibres could be decreased if specimens with longer fracture zones, i.e., panels or slabs, are used.QC 20230807</p

The Use of Slag in Accelerated Shotcrete for Rock Support : A Pilot Study on the Influence on the Early Compressive Strength

Today, the world is facing an enormous challenge where the emissions of greenhouse gases mustbe reduced significantly to stop the increasing mean temperature. For the construction industry,this challenge means that structures must be designed more carefully, and materials must be usedand produced more efficiently. Concrete is one of the most widely used materials, and cementproduction alone contributes to around 8 % of the world's total CO2 emissions. This paper presentsa pilot study in which part of the cement clinker content in accelerated shotcrete is replaced withground granulated blast furnace slag (GGBS). Shotcrete is widely used as part of the rock supportfor tunnels in hard rock and has a large cement content. Thus, the environmental impact must bereduced significantly to meet future demands. However, introducing GGBS will slow downstrength development, which is a crucial part of shotcrete. Thus, this paper aims to investigate theearly strength development, i.e., after one and seven days. The results show that an averagecompressive strength of 18 MPa can be reached after 24 hours when 35 % of the cement clinkercontent is replaced with GGBS. Finally, some important topics for further studies are pointed out.QC 20240108</p