Green inventions: Is wait-and-see a reasonable option?

We analyze the potential of different knowledge stocks to decrease the technological gap between the leader in green technology inventions and its followers in order to identify if wait-and-see is a reasonable option to benefit from knowledge. Our econometric results indicate that it is difficult to decrease the technological gap and remain competitive in the generation of green technologies without timely accumulating green knowledge. Although effects from external green knowledge stocks also contribute to decrease the technological gap, the effects are moderate and they cannot compensate the lack of internal green competences. Non-green knowledge stocks even tend to increase the technological gap

The Impact of Environmentally Friendly Innovations on Value Added

While recent literature has focused on explaining the determinants of green innovations, it is not well understood how such innovations affect performance. To analyse the relationship between green innovation and performance, new industry-level panel data were exploited: these include 12 OECD countries, the whole manufacturing sector and a period of 30 years. The results show that green inventions are U-shape related to performance. However, the turning point is quite high and hence only relevant for a few industries. This indicates that—given the current level of green promotion—market incentives alone are not sufficient to allow the green invention activities of industries to rise considerably. To verify these results and to get a better understanding of the mechanisms in the green market, we finally made several interviews with multinational firms that have a good understanding of what happens on the global market of green innovation

Inborn errors of metabolism with a focus on functional analysis of a special mutation in MCCB causing 3-Methylcrotonyl-CoA carboxylase deficiency, and MMADHC in intracellular vitamin B₁₂ metabolism, a gene in which mutations can lead to three different phenotypes

The present work focuses on two autosomal recessive inborn errors of metabolism, 3- methylcrotonyl-CoA carboxylase (MCC) deficiency, a defect in the catabolism of leucine, and on the cblD defect of intracellular vitamin B12 (cobalamin) metabolism. MCC is a heteromeric mitochondrial enzyme composed of biotin-containing α (MCCA) and smaller β (MCCB) subunits encoded by MCCA and MCCB, respectively. We report studies of the c.1054G→A mutation in exon 11 of MCCB detected in the homozygous state in a patient with MCC deficiency. Sequence analysis of MCCB cDNA revealed two overlapping transcripts, one containing the normal 73 bp of exon 11 including the missense mutation c.1054G→A (p.G352R), the other with exon 11 replaced by a 64 bp sequence from intron 10 (cryptic exon) that maintains the reading frame and is flanked by acceptable splice consensus sites. In expression studies, we show that both transcripts lack detectable MCC activity. Western blot analysis showed slightly reduced levels of MCCB using the transcript containing the missense mutation, whereas no MCCB was detected with the transcript containing the cryptic exon. Analysis of the region harboring the mutation revealed that the c.1054G→A mutation is located in an exon splice enhancer sequence. Using MCCB minigene constructs to transfect MCCB-deficient fibroblasts, we demonstrate that the reduction in utilization of exon 11 associated with the c.1054G→A mutation is due to alteration of this exon splice enhancer. Further, we show that optimization of the weak splice donor site of exon 11 corrects the splicing defect. To our knowledge, this is the first demonstration of a point mutation disrupting an exon splice enhancer that causes exon skipping along with utilization of a cryptic exon. In man, cobalamin is an essential cofactor in only two metabolic pathways. Intracellular conversion of cobalamin to its two coenzymes, adenosylcobalamin (AdoCbl) in mitochondria and methylcobalamin (MeCbl) in the cytoplasm, is necessary for the homeostasis of methylmalonic acid and homocysteine. We have identified the MMADHC gene responsible for the cblD defect that can cause isolated methylmalonic aciduria, isolated homocystinuria, or both. Various mutations are associated with each of the three biochemical phenotypes of the disorder. Using expression vectors containing the wildtype MMADHC with an enhanced mitochondrial leader sequence, mutations changing possible downstream sites of reinitiation or mutations introducing stop codons, we provide evidence that reinitiation of translation at downstream AUGs explains most of the phenotypes found in cblD patients. Furthermore, our data indicate that the sequence after Met116 is sufficient for MeCbl synthesis whereas the sequence between Met62 and Met116 is required for AdoCbl synthesis. Our findings support the hypothesis that a delicate balance exists between cytosolic MeCbl and mitochondrial AdoCbl synthesis, supporting the role of the MMADHC protein as a branching point in intracellular cobalamin trafficking. ZUSAMMENFASSUNG Die vorliegende Arbeit beschäftigt sich mit zwei autosomal rezessiv vererbten Stoffwechselkrankheiten, dem 3-Methylcrotonyl-CoA Carboxylase (MCC) Mangel, welches ein Defekt im Leuzin-Abbau ist, und dem cblD Defekt, einer Störung des intrazellulären Vitamin B12 (Cobalamin) Stoffwechsels. MCC ist ein heteromeres mitochondriales Enzym aus Biotin-bindenden α (MCCA) und kleineren β (MCCB) Untereinheiten, welche durch MCCA und MCCB kodiert sind. Wir berichten über die Mutation c.1054G>A (p.G352R) in Exon 11 von MCCB, welche wir homozygot bei einem MCC-Patienten gefunden haben. Die Analyse der cDNA Sequenz von MCCB ergab zwei überlappende Transkripte: eines mit der Mutation c.1054G>A, sowie ein weiteres mit Ersatz der 73 bp von Exon 11 durch 64 bp aus Intron 10. Dieses kryptische Exon verändert das Leseraster nicht und weist akzeptable Spleiss-Stellen auf. Expressionsstudien zeigen, dass beide Transkripte keine MCC Aktivität besitzen bei nur reduzierter Proteinmenge beim mutationstragenden Transkript sowie Proteinverlust des Transkriptes mit kryptischem Exon. Die Mutation c.1054G>A ist Teil eines Exon-Spleiss- Enhancers. Transfektionsexperimente von MCCB Minigen Konstrukten in MCCB defizienten Fibroblasten zeigten bei Veränderung des Exon-Spleiss-Enhancers ein vermindertes Spleissen von Exon 11. Zudem konnte bei Sequenz-Optimierung der Exon 11-Spleiss- Stellen der Spleiss-Defekt korrigiert werden. Unseres Wissens ist dies der erste Nachweis eines durch Punktmutation in einem Exon-Spleiss-Enhancer resultierenden Exonverlustes bei gleichzeitiger Insertion eines kryptischen Exons. Beim Menschen wird Cobalamin für nur zwei Reaktionsschritte des Stoffwechsels benötigt: als mitochondriales Adenosylcobalamin (AdoCbl) für den Abbau von Methylmalonsäure und als zytosolisches Methylcobalamin (MeCbl) für die Methylierung von Homocystein. Bei Vorliegen eines cblD-Defektes besteht eine Methylmalonazidurie, eine Hyperhomocysteinämie oder eine Kombination aus beiden Symptomen. Uns gelang die Klonierung des MMADHC Gens, welches für den cblD Defekt verantwortlich ist. Verschiedene Mutationen sind mit den drei Phänotypen des cblD-Defektes assoziiert. Durch Veränderung der mitochondrialen Importsequenz, durch Korrektur der zusätzlichen AUGs (Transkriptions-Start) und durch Einfügen weiterer Stop-Mutationen konnte gezeigt werden, dass eine Reinitiation der Transkription an weiteren AUGs die in cblD Patienten gefundenen Phänotypen erklären könnte. Weiter haben wir Hinweise darauf, dass ein cblD-Protein mit Beginn bei Met116 weiter MeCbl synthetisieren kann, und dass die Sequenz zwischen Met62 und Met116 notwendig für die Synthese von AdoCbl ist. Unsere Resultate bestätigen die Hypothese eines kritischen Gleichgewichts zwischen zytosolischer MeCbl und mitochondrialer AdoCbl Synthese. Das MMADHC Protein spielt somit eine wichtige Rolle bei der intrazellulären Cobalamin Verteilung

Policy instruments and self-reported impacts of the adoption of energy saving technologies in the DACH region

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Cryptic Exon Activation by Disruption of Exon Splice Enhancer

3-Methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine catabolism. MCC is a heteromeric mitochondrial enzyme composed of biotin-containing α (MCCA) and smaller β (MCCB) subunits encoded by MCCA and MCCB, respectively. We report studies of the c.1054G→A mutation in exon 11 of MCCB detected in the homozygous state in a patient with MCC deficiency. Sequence analysis of MCCB cDNA revealed two overlapping transcripts, one containing the normal 73 bp of exon 11 including the missense mutation c.1054G→A (p.G352R), the other with exon 11 replaced by a 64-bp sequence from intron 10 (cryptic exon 10a) that maintains the reading frame and is flanked by acceptable splice consensus sites. In expression studies, we show that both transcripts lack detectable MCC activity. Western blot analysis showed slightly reduced levels of MCCB using the transcript containing the missense mutation, whereas no MCCB was detected with the transcript containing the cryptic exon 10a. Analysis of the region harboring the mutation revealed that the c.1054G→A mutation is located in an exon splice enhancer sequence. Using MCCB minigene constructs to transfect MCCB-deficient fibroblasts, we demonstrate that the reduction in utilization of exon 11 associated with the c.1054G→A mutation is due to alteration of this exon splice enhancer. Further, we show that optimization of the weak splice donor site of exon 11 corrects the splicing defect. To our knowledge, this is the first demonstration of a point mutation disrupting an exon splice enhancer that causes exon skipping along with utilization of a cryptic exon

ICF Core Sets for early post-acute rehabilitation facilities

OBJECTIVE: To identify candidate categories for International Classification of Functioning, Disability and Health (ICF) Core Sets for the reporting and measurement of functioning in patients in early post-acute rehabilitation facilities. DESIGN: Prospective multi-centre cohort study. PATIENTS: Patients receiving rehabilitation interventions for musculoskeletal, neurological or cardiopulmonary injury or disease in early post-acute rehabilitation facilities. METHODS: Functioning was coded using the ICF. The criterion for selecting candidate categories for the ICF Core Sets was based on their ability to discriminate between patients with high or low functioning status. Discrimination was assessed using multivariable regression models, the independent variables being all of the ICF categories of the respective comprehensive ICF Core Set. Analogue ratings of overall functioning as reported by patients and health professionals were used as dependent variables. RESULTS: A total of 165 patients were included in the study (67 neurological, 37 cardiopulmonary, 61 musculoskeletal), mean age 67.5 years, 46.1 female. Selection yielded 38 cate-gories for neurological, 32 for cardiopulmonary, and 31 for musculoskeletal. CONCLUSION: The present selection of categories can be considered an initial proposal, serving to identify the issues most relevant for the assessment and monitoring of functioning in patients undergoing early post-acute rehabilitation for neurological, cardiopulmonary, and musculoskeletal conditions

ICF Core Sets for early post-acute rehabilitation facilities

OBJECTIVE: To identify candidate categories for International Classification of Functioning, Disability and Health (ICF) Core Sets for the reporting and measurement of functioning in patients in early post-acute rehabilitation facilities. DESIGN: Prospective multi-centre cohort study. PATIENTS: Patients receiving rehabilitation interventions for musculoskeletal, neurological or cardiopulmonary injury or disease in early post-acute rehabilitation facilities. METHODS: Functioning was coded using the ICF. The criterion for selecting candidate categories for the ICF Core Sets was based on their ability to discriminate between patients with high or low functioning status. Discrimination was assessed using multivariable regression models, the independent variables being all of the ICF categories of the respective comprehensive ICF Core Set. Analogue ratings of overall functioning as reported by patients and health professionals were used as dependent variables. RESULTS: A total of 165 patients were included in the study (67 neurological, 37 cardiopulmonary, 61 musculoskeletal), mean age 67.5 years, 46.1 female. Selection yielded 38 cate-gories for neurological, 32 for cardiopulmonary, and 31 for musculoskeletal. CONCLUSION: The present selection of categories can be considered an initial proposal, serving to identify the issues most relevant for the assessment and monitoring of functioning in patients undergoing early post-acute rehabilitation for neurological, cardiopulmonary, and musculoskeletal conditions

Brief ICF Core Set for patients in geriatric post-acute rehabilitation facilities

OBJECTIVE: To identify candidate categories for International Classification of Functioning, Disability and Health (ICF) Core Sets for the reporting and clinical measurement of functioning in older patients in early post-acute rehabilitation facilities. DESIGN: Prospective multi-centre cohort study. PATIENTS: Older patients receiving rehabilitation interventions in early post-acute rehabilitation facilities. METHODS: Functioning was coded using the ICF. The criterion for selecting candidate categories for the brief ICF Core Sets was based on their ability to discriminate between patients with high or low functioning status. Discrimination was assessed using multivariable regression models, the independent variables being all of the ICF categories of the respective comprehensive ICF Core Set. Analogue ratings of overall functioning as reported by patients and health professionals were used as dependent variables. RESULTS: A total of 209 patients were included in the study, mean age 80.4 years, 67.0 female. Selection yielded a total of 29 categories for the functioning part and 9 categories for the contextual part of the ICF. CONCLUSION: The present selection of categories can be considered an initial proposal, serving to identify the issues most relevant for the clinical assessment and monitoring of functioning in older patients undergoing early post-acute rehabilitation

Brief ICF Core Set for patients in geriatric post-acute rehabilitation facilities

OBJECTIVE: To identify candidate categories for International Classification of Functioning, Disability and Health (ICF) Core Sets for the reporting and clinical measurement of functioning in older patients in early post-acute rehabilitation facilities. DESIGN: Prospective multi-centre cohort study. PATIENTS: Older patients receiving rehabilitation interventions in early post-acute rehabilitation facilities. METHODS: Functioning was coded using the ICF. The criterion for selecting candidate categories for the brief ICF Core Sets was based on their ability to discriminate between patients with high or low functioning status. Discrimination was assessed using multivariable regression models, the independent variables being all of the ICF categories of the respective comprehensive ICF Core Set. Analogue ratings of overall functioning as reported by patients and health professionals were used as dependent variables. RESULTS: A total of 209 patients were included in the study, mean age 80.4 years, 67.0 female. Selection yielded a total of 29 categories for the functioning part and 9 categories for the contextual part of the ICF. CONCLUSION: The present selection of categories can be considered an initial proposal, serving to identify the issues most relevant for the clinical assessment and monitoring of functioning in older patients undergoing early post-acute rehabilitation

Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism

The cblD defect of intracellular vitamin B12 metabolism can lead to isolated methylmalonic aciduria (cblD-MMA) or homocystinuria (cblD-HC), or combined methylmalonic aciduria and homocystinuria (cblD-MMA/HC). We studied the mechanism whereby MMADHC mutations can lead to three phenotypes. The effect of various expression vectors containing MMADHC modified to contain an enhanced mitochondrial leader sequence or mutations changing possible downstream sites of reinitiation of translation or mutations introducing stop codons on rescue of adenosyl- and methylcobalamin (MeCbl) formation was studied. The constructs were transfected into cell lines derived from various cblD patient's fibroblasts. Expression of 10 mutant alleles from 15 cblD patients confirmed that the nature and location of the mutations correlate with the biochemical phenotype. In cblD-MMA/HC cells, improving mitochondrial targeting of MMADHC clearly increased the formation of adenosylcobalamin (AdoCbl) with a concomitant decrease in MeCbl formation. In cblD-MMA cells, this effect was dependent on the mutation and showed a negative correlation with endogenous MMADHC mRNA levels. These findings support the hypothesis that a single protein exists with two different functional domains that interact with either cytosolic or mitochondrial targets. Also a delicate balance exists between cytosolic MeCbl and mitochondrial AdoCbl synthesis, supporting the role of cblD protein as a branch point in intracellular cobalamin trafficking. Furthermore, our data indicate that the sequence after Met116 is sufficient for MeCbl synthesis, whereas the additional sequence between Met62 and Met116 is required for AdoCbl synthesis. Accordingly, western blot studies reveal proteins of the size expected from the stop codon position with subsequent reinitiation of translatio