| 1. |
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| 2. |
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| 3. |
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| 4. |
- Eisfeldt, J., et al.
(författare)
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Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements
- 2019
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Ingår i: PLOS Genetics. - : NLM (Medline). - 1553-7390 .- 1553-7404. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Complex chromosomal rearrangements (CCRs) are rearrangements involving more than two chromosomes or more than two breakpoints. Whole genome sequencing (WGS) allows for outstanding high resolution characterization on the nucleotide level in unique sequences of such rearrangements, but problems remain for mapping breakpoints in repetitive regions of the genome, which are known to be prone to rearrangements. Hence, multiple complementary WGS experiments are sometimes needed to solve the structures of CCRs. We have studied three individuals with CCRs: Case 1 and Case 2 presented with de novo karyotypically balanced, complex interchromosomal rearrangements (46,XX,t(2;8;15)(q35;q24.1;q22) and 46,XY,t(1;10;5)(q32;p12;q31)), and Case 3 presented with a de novo, extremely complex intrachromosomal rearrangement on chromosome 1. Molecular cytogenetic investigation revealed cryptic deletions in the breakpoints of chromosome 2 and 8 in Case 1, and on chromosome 10 in Case 2, explaining their clinical symptoms. In Case 3, 26 breakpoints were identified using WGS, disrupting five known disease genes. All rearrangements were subsequently analyzed using optical maps, linked-read WGS, and short-read WGS. In conclusion, we present a case series of three unique de novo CCRs where we by combining the results from the different technologies fully solved the structure of each rearrangement. The power in combining short-read WGS with long-molecule sequencing or optical mapping in these unique de novo CCRs in a clinical setting is demonstrated.
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| 5. |
- Enervald, E, et al.
(författare)
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A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination
- 2013
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 210:12, s. 2503-2513
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Tidskriftsartikel (refereegranskat)abstract
- DNA double strand breaks (DSBs) are mainly repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ). These breaks pose severe threats to genome integrity but can also be necessary intermediates of normal cellular processes such as immunoglobulin class switch recombination (CSR). During CSR, DSBs are produced in the G1 phase of the cell cycle and are repaired by the classical NHEJ machinery. By studying B lymphocytes derived from patients with Cornelia de Lange Syndrome, we observed a strong correlation between heterozygous loss-of-function mutations in the gene encoding the cohesin loading protein NIPBL and a shift toward the use of an alternative, microhomology-based end joining during CSR. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Association of NIPBL deficiency and impaired NHEJ was also observed in a plasmid-based end-joining assay and a yeast model system. Our results suggest that NIPBL plays an important and evolutionarily conserved role in NHEJ, in addition to its canonical function in sister chromatid cohesion and its recently suggested function in HR.
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| 11. |
- Becker, M, et al.
(författare)
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Presynaptic dysfunction in CASK-related neurodevelopmental disorders
- 2020
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1, s. 312-
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Tidskriftsartikel (refereegranskat)abstract
- CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory–inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.
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| 12. |
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| 13. |
- Nilsson, D., et al.
(författare)
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Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation
- 2017
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 38:2, s. 180-192
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Tidskriftsartikel (refereegranskat)abstract
- Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15% of the interchromosomal translocation events.
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| 14. |
- Wincent, J, et al.
(författare)
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CHD7 mutation spectrum in 28 Swedish patients diagnosed with CHARGE syndrome
- 2008
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 74:1, s. 31-38
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Tidskriftsartikel (refereegranskat)abstract
- CHARGE syndrome is a disorder characterized by Coloboma, Heart defect, Atresia choanae, Retarded growth and/or development, Genital hypoplasia and Ear anomalies. Heterozygous mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene have been identified in about 60% of individuals diagnosed with CHARGE syndrome. We performed a CHD7 mutation screening by direct exon sequencing in 28 index patients (26 sporadic cases, 1 familial case consisting of a brother and sister and 1 case consisting of monozygotic twins) diagnosed with CHARGE syndrome in order to determine the mutations in a cohort of Swedish CHARGE syndrome patients. The patients without a detectable CHD7 mutation, or with a missense mutation, were further investigated by multiplex ligation-dependent probe amplification (MLPA) in order to search for intragenic deletions or duplications. Thirteen novel mutations and five previously reported mutations were detected. The mutations were scattered throughout the gene and included nonsense, frameshift and missense mutations as well as intragenic deletions. In conclusion, CHD7 mutations were detected in a large proportion (64%) of cases diagnosed with CHARGE syndrome. Screening for intragenic deletions with MLPA is recommended in cases where mutations are not found by sequencing. In addition, a CDH7 mutation was found in an individual without temporal bone malformation.
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| 18. |
- Wincent, J, et al.
(författare)
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Erratum
- 2016
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Ingår i: Molecular genetics & genomic medicine. - : Wiley. - 2324-9269. ; 4:3, s. 367-367
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 19. |
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| 20. |
- Wincent, J, et al.
(författare)
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Sixteen New Cases Contributing to the Characterization of Patients with Distal 22q11.2 Microduplications
- 2010
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Ingår i: Molecular syndromology. - : S. Karger AG. - 1661-8769 .- 1661-8777. ; 1:5, s. 246-254
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Tidskriftsartikel (refereegranskat)abstract
- The chromosome region 22q11.2 has long been recognized to be susceptible to genomic rearrangement. More recently, this genomic instability has been shown to extend distally (involving LCR22E–H) to the commonly deleted/duplicated region. To date, 21 index cases with ‘distal’ 22q11.2 duplications have been reported. We report on the clinical and molecular characterization of 16 individuals with distal 22q11.2 duplications identified by DNA microarray analysis. Two of the individuals have been partly described previously. The clinical phenotype varied among the patients in this study, although the majority displayed various degrees of developmental delay and speech disturbances. Other clinical features included behavioral problems, hypotonia, and dysmorphic facial features. Notably, none of the patients was diagnosed with a congenital heart defect. We found a high degree of inherited duplications. Additional copy number changes of unclear clinical significance were identified in 5 of our patients, and it is possible that these may contribute to the phenotypic expression in these patients as has been suggested recently in a 2-hit ‘digenic’ model for 16p12.1 deletions. The varied phenotypic expression and incomplete penetrance observed for distal 22q11.2 duplications makes it exceedingly difficult to ascribe pathogenicity for these duplications. Given the observed enrichment of the duplication in patient samples versus healthy controls, it is likely that distal 22q11.2 duplications represent a susceptibility/risk locus for speech and mild developmental delay.
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| 21. |
- Arbuthnott, A., et al.
(författare)
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Reduced opportunities for regional renewal : The role of rigid threat responses
- 2011
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Ingår i: Entrepreneurship and Regional Development. - : Informa UK Limited. - 0898-5626 .- 1464-5114. ; 23:7-8, s. 603-635
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Tidskriftsartikel (refereegranskat)abstract
- This article illustrates how opportunities for regional renewal in a peripheral region may be reduced by rigid threat responses undertaken by established firms operating within traditional regional industry. In an inductive case study of new biorefinery industry initiatives in a region where traditional pulp-and-paper and forestry industry was in decline, we used primary and secondary data to outline how a set of new industry players who created innovative ways of using existing regional infrastructures and resources sparked rigid threat responses among established firms from the struggling traditional industry. Established industry firms framed new industry initiatives as threats, and responded by (1) reducing new industry actors' possibilities for new business development, (2) engaging in entrenched resistance, (3) creating collaborative illusions and (4) undermining the fundamentals of the new industry. Consequently, this study contributes to existing literature by proposing the potential of applying the threat-rigidity thesis on a regional level. This is achieved by illustrating that conflicting behaviours between new and established regional industry actors constrain opportunities for regional renewal in a peripheral region. As such, relevant directions for future research and policy implications are outlined
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| 22. |
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| 23. |
- Cardon, M., et al.
(författare)
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Entrepreneurial passion : a theoretical framework for the study of emotion in entrepreneurship
- 2004
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Ingår i: Frontiers of Entrepreneurship Research 2004. - : Babson College Center.
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Konferensbidrag (refereegranskat)abstract
- Principal TopicPassion has long been recognized as a central component of entrepreneurial motivation and success. Yet surprising little systematic theoretical or empirical work exists concerning the notion of passion and its influence on entrepreneurial activities. Passion has been viewed as both cognitive and emotional, as both a trait and a state, and many scholars do not distinguish between passion as an emotion and the consequences of such passion, such as working longer hours. Thus there is great lack of clarity in defining exactly what passion is, what it feels like, and its role in entrepreneurship.We build a conceptual model of emotion in entrepreneurship, drawing from a strong foundation in the psychological and sociological literatures. In this model, we separate the experience of emotion from the outcomes of such emotional experiences, and distinguish between the distal outcome of entrepreneurial effectiveness, which involves attainment of venture and individual goals, and the drivers of such effectiveness, including problem-solving, persistence, and absorption, which are behaviors that directly result from emotional experiences. Third, we distinguish between situation-specific and more enduring emotional experiences, and suggest that both sets of emotions impact entrepreneurial outcomes. For both episodic and enduring emotions, individuals have certain stable emotional tendencies (core affect), ventures have the ability to engender specific emotions due to their specific nature (affective qualities), and both of these combine to create the subconscious (attributed affect) and conscious (emotional meta-experience) emotional experiences. Since the current emotional state may differ from the more enduring state, this potential discrepancy between them is modeled. If such a discrepancy exists, the tension between the episodic emotional experience and the enduring one must be managed by the entrepreneur, through the process of emotional regulation.Results and ImplicationsBy developing the theoretical foundation for emotional influence in this domain, we enrich theory on entrepreneurial passion and provide concrete guidelines to spur entrepreneurial effectiveness. In particular we suggest how incorporating entrepreneurial emotion in models of entrepreneurship will shed light on how to better prepare nascent and early-stage entrepreneurs for the challenges that lie ahead of them, and how to enhance their own persistence and effectiveness.
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| 24. |
- Diaz, Oscar E., et al.
(författare)
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Perfluorooctanesulfonic acid modulates barrier function and systemic T-cell homeostasis during intestinal inflammation
- 2021
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Ingår i: DMM Disease Models and Mechanisms. - : The Company of Biologists. - 1754-8411 .- 1754-8403. ; 14:12, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- The intestinal epithelium is continuously exposed to deleterious environmental factors that might cause aberrant immune responses leading to inflammatory disorders. However, what environmental factors might contribute to disease are poorly understood. Here, to overcome the lack of in vivo models suitable for screening of environmental factors, we used zebrafish reporters of intestinal inflammation. Using zebrafish, we interrogated the immunomodulatory effects of polyfluoroalkyl substances, which have been positively associated with ulcerative colitis incidence. Exposure to perfluorooctanesulfonic acid (PFOS) during 2,4,6-trinitro-benzene sulfonic acid (TNBS)-induced inflammation enhanced the expression of proinflammatory cytokines as well as neutrophil recruitment to the intestine of zebrafish larvae, which was validated in the TNBS-induced colitis mouse model. Moreover, PFOS exposure in mice undergoing colitis resulted in neutrophil-dependent increased intestinal permeability and enhanced PFOS translocation into the circulation. This was associated with a neutrophil-dependent expansion of systemic CD4+ T cells. Thus, our results indicate that PFOS worsens inflammation-induced intestinal damage with disruption of T-cell homeostasis beyond the gut and provides a novel in vivo toolbox to screen for pollutants affecting intestinal homeostasis.
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| 27. |
- Fergelot, Patricia, et al.
(författare)
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Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations
- 2016
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Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 170:12, s. 3069-3082
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Tidskriftsartikel (refereegranskat)abstract
- Rubinstein–Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8–10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype–phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia.
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| 28. |
- Fredström, A., et al.
(författare)
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Tracking innovation diffusion : AI analysis of large-scale patent data towards an agenda for further research
- 2021
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Ingår i: Technological forecasting & social change. - : Elsevier. - 0040-1625 .- 1873-5509. ; 165
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in AI algorithms and computational power have led to opportunities for new methods and tools. Particularly when it comes to detecting the current status of inter-industry technologies, the new tools can be of great assistance. This is important because the research focus has been on how firms generate value through managing their business models. However, further attention needs to be given to the external technological opportunities that also contribute to value creation in firms. We applied unsupervised machine learning techniques, particularly DBSCAN, in an attempt to generate a macro-level technological map. Our results show that AI and machine learning tools can indeed be used for these purposes, and DBSCAN is a potential algorithm. Further research is needed to improve the maps and to use the generated data to study related phenomena including entrepreneurship.
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| 29. |
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| 31. |
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| 33. |
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| 34. |
- Vaz, R, et al.
(författare)
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A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy
- 2022
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- The pyruvate dehydrogenase complex (PDC) is responsible for the conversion of pyruvate into acetyl-CoA, which is used for energy conversion in cells. PDC activity is regulated by phosphorylation via kinases and phosphatases (PDK/PDP). Variants in all subunits of the PDC and in PDK3 have been reported, with varying phenotypes including lactic acidosis, neurodevelopmental delay, peripheral neuropathy, or seizures. Here, we report a de novo heterozygous missense variant in PDK1 (c.1139G > A; p.G380D) in a girl with developmental delay and early onset severe epilepsy. To investigate the role of PDK1G380D in energy metabolism and neuronal development, we used a zebrafish model. In zebrafish embryos we show a reduced number of cells with mitochondria with membrane potential, reduced movements, and a delay in neuronal development. Furthermore, we observe a reduction in the phosphorylation of PDH-E1α by PDKG380D, which suggests a disruption in the regulation of PDC activity. Finally, in patient fibroblasts, a mild reduction in the ratio of phosphorylated PDH over total PDH-E1α was detected. In summary, our findings support the notion that this aberrant PDK1 activity is the cause of clinical symptoms in the patient.
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| 35. |
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| 36. |
- Vesalainen, J., et al.
(författare)
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Purchasers as boundary spanners : Mapping purchasing agents' persuasive orientations
- 2020
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Ingår i: Industrial Marketing Management. - : Elsevier. - 0019-8501 .- 1873-2062. ; 84, s. 224-236
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Tidskriftsartikel (refereegranskat)abstract
- This study introduces a framework of persuasive communication that is central to understanding how individual purchasers behave as boundary spanners to manage customer–supplier relationships. Drawing on the institutional theory and multiple governance approach, we assume authoritarian, competitive, and relational behavioral orientations reflect institutional logics at an individual level. Purchasers' boundary-spanner behavior thus manifests itself as individual purchasers' rhetorical orientations. In a sample of 349 purchasers, we find support for the existence of four configurations of orientations: competitive/authoritarian, relational, comprehensive, and neutral. A subsequent follow-up study of 20 interviews with the most typical representatives of each group suggests storylines that reflect the background and logic of different persuasive styles. The findings highlight purchaser persuasive orientation as one facet of a purchaser capability set making it possible to cope with the transactional versus relational paradox in buyer–seller relationship contexts.
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| 37. |
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| 38. |
- Wincent, Emma, et al.
(författare)
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Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner
- 2016
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 110, s. 117-129
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Tidskriftsartikel (refereegranskat)abstract
- 6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, blocked swim bladder inflation, and strongly potentiated expression of Ahr2-regulated genes. These effects were substantially reduced in embryos with a combined knockdown of Ahr2 and CYP1A, indicating that the toxicity was mediated at least partly by Ahr2. Co-exposure to the CYP1 inhibitor alpha-naphthoflavone (αNF) and FICZ had similar effects as the combination of CYP1A-MO and FICZ. HPLC analysis of FICZ-exposed embryos showed increased levels of FICZ after concomitant CYP1A-MO injection or αNF co-exposure. Together, these results show that a functioning CYP1/AHR feedback loop is crucial for regulation of AHR signaling by a potential physiological ligand in vivo and further highlights the role of CYP1 enzymes in regulating biological effects of FICZ.
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| 39. |
- Wincent, Emma, et al.
(författare)
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Combination effects of AHR agonists and Wnt/beta-catenin modulators in zebrafish embryos : Implications for physiological and toxicological AHR functions
- 2015
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 284:2, s. 163-179
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Tidskriftsartikel (refereegranskat)abstract
- Wnt/beta-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between beta-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the beta-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3',4,4',5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with beta-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of p-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a beta-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in the presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholino-oligonudeotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of beta-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of p-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating beta-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.
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