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Contains fulltext : 182555.pdf (publisher's version ) (Closed access), Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

Item does not contain fulltext, Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to beta-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA br

Contains fulltext : 182555.pdf (publisher's version ) (Closed access), Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

Item does not contain fulltext, Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to beta-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

Item does not contain fulltext, Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to beta-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

Contains fulltext : 182555.pdf (publisher's version ) (Closed access), Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

Item does not contain fulltext, We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

Item does not contain fulltext, We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

Contains fulltext : 153277.pdf (Publisher’s version ) (Open Access), We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

An all-titanium dimensionally stable anode (DSA) electrocatalyst has been developed for the electrowinning of Cu, Ni, Co and Zn. The anode consists of a hanger bar with vertical distributor bars to which primary Ti mesh is attached by weldments, the active mesh being coated with electrocatalytic iridium and/or ruthenium oxide obtained by the thermal decomposition of precursor solutions applied to the titanium substrates. At processing temperatures in excess of 450 degrees C, highly electrochemically active DSA anodes that have a quasi-amorphous phase were obtained. Advantages of the DSA anodes include energy savings of 0.3-0.55 V over conventional lead-alloy anodes, elimination of Co electrolyte addition required for Pb anodes, improvement of the anode catalytic activity by about 80 mV by modification of the noble-metal crystallite lattice and crystalline size without decreasing the coating decomposition temperature, and the elimination of sludge generation., An all-titanium dimensionally stable anode (DSA) electrocatalyst has been developed for the electrowinning of Cu, Ni, Co and Zn. The anode consists of a hanger bar with vertical distributor bars to which primary Ti mesh is attached by weldments, the active mesh being coated with electrocatalytic iridium and/or ruthenium oxide obtained by the thermal decomposition of precursor solutions applied to the titanium substrates. At processing temperatures in excess of 450 degrees C, highly electrochemically active DSA anodes that have a quasi-amorphous phase were obtained. Advantages of the DSA anodes include energy savings of 0.3-0.55 V over conventional lead-alloy anodes, elimination of Co electrolyte addition required for Pb anodes, improvement of the anode catalytic activity by about 80 mV by modification of the noble-metal crystallite lattice and crystalline size without decreasing the coating decomposition temperature, and the elimination of sludge generation.

The dimensionally stable anodes (DSA) consist of a hanger bar and vertical distributor bars with primary Ti mesh attached by weldments. The active mesh has noble metal electrocatalytic coatings consisting of Ir and/or Ru oxides obtained by the thermal decomposition of precursor solutions applied to the Ti substrate. The catalytic activity of the anodes is increased by controlling the crystallite size of the noble metals without reducing the decomposition temperature. Optimum conditions have been determined for the production of a highly active anode consisting of a quasi-amorphous phase obtained at high temperatures above 450 degrees C in order to ensure the stability of the oxides and their lifetime performance. The Pb-free anodes provide Pb-free cathode quality and energy savings of 0.3-0.55 V, eliminate the need for the Co sulphate additions required for Pb anodes in Cu electrowinning, increase plant cathode output through higher current density operations and no sludge is generated. DSA anodes can be employed for the electrowinning of Cu, Ni, Co and Zn., The dimensionally stable anodes (DSA) consist of a hanger bar and vertical distributor bars with primary Ti mesh attached by weldments. The active mesh has noble metal electrocatalytic coatings consisting of Ir and/or Ru oxides obtained by the thermal decomposition of precursor solutions applied to the Ti substrate. The catalytic activity of the anodes is increased by controlling the crystallite size of the noble metals without reducing the decomposition temperature. Optimum conditions have been determined for the production of a highly active anode consisting of a quasi-amorphous phase obtained at high temperatures above 450 degrees C in order to ensure the stability of the oxides and their lifetime performance. The Pb-free anodes provide Pb-free cathode quality and energy savings of 0.3-0.55 V, eliminate the need for the Co sulphate additions required for Pb anodes in Cu electrowinning, increase plant cathode output through higher current density operations and no sludge is generated. DSA anodes can be employed for the electrowinning of Cu, Ni, Co and Zn.

Mesh-on-lead anodes consist of standard Pb-Sn-Ca anodes coupled with an electrocatalytic coating on a Ti mesh. The development of a corrosion- resistant attachment method and a nanocrystalline coating tolerant of current reversals has produced mesh-on-lead anodes that have been demonstrated to be robust and capable of long-term service in a Cu electrowinning environment, having been used in a commercial facility for about three years. The stabilised ruthenium oxide coating has resulted in average voltage savings of more than 200 mV over standard Pb-alloy anodes., Mesh-on-lead anodes consist of standard Pb-Sn-Ca anodes coupled with an electrocatalytic coating on a Ti mesh. The development of a corrosion- resistant attachment method and a nanocrystalline coating tolerant of current reversals has produced mesh-on-lead anodes that have been demonstrated to be robust and capable of long-term service in a Cu electrowinning environment, having been used in a commercial facility for about three years. The stabilised ruthenium oxide coating has resulted in average voltage savings of more than 200 mV over standard Pb-alloy anodes.

The ability to electrowin high grade copper from cobalt-free electrolyte using MOL (mesh-on-lead) anodes was demonstrated both in continuously operated bench cells and a full-size industrial test facility. Advantages include a very high quality cathode , reduced power consumption, improved current efficiency and lead sludge elimination., The ability to electrowin high grade copper from cobalt-free electrolyte using MOL (mesh-on-lead) anodes was demonstrated both in continuously operated bench cells and a full-size industrial test facility. Advantages include a very high quality cathode , reduced power consumption, improved current efficiency and lead sludge elimination.

A retrofittable, low-cost anode has been developed by attaching disposable, electrocatalytically active titanium mesh over the existing lead anodes. The electrocatalytically active coating on the mesh is typically a PGM oxide such as RuO2 or IrO2, usually with valve metal oxides such as TiO2 or Ta2O5. The coated-mesh anode operates at potentials several hundred millivolts lower than the lead anode, providing significant power savings. As most of the current flows through the mesh, the exposed lead surfaces are stabilised, sludge formation is virtually eliminated and the purity of the plated copper is greatly enhanced; it is also more uniform with minimal formation of dendrites, reducing short-circuiting. Further savings may be realised by the elimination of non-essential chemicals such as cobalt. When necessary, the mesh can be replaced completely or in small sections., A retrofittable, low-cost anode has been developed by attaching disposable, electrocatalytically active titanium mesh over the existing lead anodes. The electrocatalytically active coating on the mesh is typically a PGM oxide such as RuO2 or IrO2, usually with valve metal oxides such as TiO2 or Ta2O5. The coated-mesh anode operates at potentials several hundred millivolts lower than the lead anode, providing significant power savings. As most of the current flows through the mesh, the exposed lead surfaces are stabilised, sludge formation is virtually eliminated and the purity of the plated copper is greatly enhanced; it is also more uniform with minimal formation of dendrites, reducing short-circuiting. Further savings may be realised by the elimination of non-essential chemicals such as cobalt. When necessary, the mesh can be replaced completely or in small sections.

Relevant UK legislation and developments in other countries are identified and an attempt is made to clarify the implications for actual or potential liabilities and costs. While there is legislation of direct application to the pyrometallurgical industry, such as the EU Framework Directive on combatting air pollution from industrial plants (84/360/EEC), the prospect of legislation currently directed at other industries being applied to pyrometallurgical processes cannot be ignored. In England and Wales the Environmental Protection Act 1990 is the most significant source of legislation, regulating air and water pollution, while management of landfill waste disposal is delegated to the county waste regulation authorities. Waste management facilities are licensed under the 1994 regulations; points for preliminary consideration by potential operators include choice of leachability testing method and the possibility of producing designer wastes. Forward planning for plant decommissioning and rehabilitation is also crucial. Despite the "polluter pays" principle, the costs of pollution are borne by society as consumers, taxpayers or victims; legislation is shifting the emphasis on to the consumer., Relevant UK legislation and developments in other countries are identified and an attempt is made to clarify the implications for actual or potential liabilities and costs. While there is legislation of direct application to the pyrometallurgical industry, such as the EU Framework Directive on combatting air pollution from industrial plants (84/360/EEC), the prospect of legislation currently directed at other industries being applied to pyrometallurgical processes cannot be ignored. In England and Wales the Environmental Protection Act 1990 is the most significant source of legislation, regulating air and water pollution, while management of landfill waste disposal is delegated to the county waste regulation authorities. Waste management facilities are licensed under the 1994 regulations; points for preliminary consideration by potential operators include choice of leachability testing method and the possibility of producing designer wastes. Forward planning for plant decommissioning and rehabilitation is also crucial. Despite the "polluter pays" principle, the costs of pollution are borne by society as consumers, taxpayers or victims; legislation is shifting the emphasis on to the consumer.

Most guidance on environmental assessment, of which impact assessment is only a part, is either very general or deals with procedures rather than techniques. Research in the UK showed a rise in satisfactory environmental statements from 34% in 1989 to 60% in 1991, but 23% were still poor or very poor. Most assessments rely too much on description and have too little analysis, while many environmental statements are prepared without proper assessment instead of following the planning and design stages of a project. Environmental assessment has four stages: identification, prediction, interpretation and communication. Scope definition to identify relevant potential impacts is crucial, with sensitivity analysis a useful tool. A baseline, of the required data only, must then be established. The effects predicted and assessed for their consequences must be those after mitigation measures, which should be described, have been taken., Most guidance on environmental assessment, of which impact assessment is only a part, is either very general or deals with procedures rather than techniques. Research in the UK showed a rise in satisfactory environmental statements from 34% in 1989 to 60% in 1991, but 23% were still poor or very poor. Most assessments rely too much on description and have too little analysis, while many environmental statements are prepared without proper assessment instead of following the planning and design stages of a project. Environmental assessment has four stages: identification, prediction, interpretation and communication. Scope definition to identify relevant potential impacts is crucial, with sensitivity analysis a useful tool. A baseline, of the required data only, must then be established. The effects predicted and assessed for their consequences must be those after mitigation measures, which should be described, have been taken.