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The chromatin remodeler ALC1 is activated by DNA damage-induced poly(ADP-ribose) deposited by PARP1/PARP2 and their co-factor HPF1. ALC1 has emerged as a cancer drug target, but how it is recruited to ADP-ribosylated nucleosomes to affect their positioning near DNA breaks is unknown. Here we find that PARP1/HPF1 preferentially initiates ADP-ribosylation on the histone H2B tail closest to the DNA break. To dissect the consequences of such asymmetry, we generate nucleosomes with a defined ADP-ribosylated H2B tail on one side only. The cryo-electron microscopy structure of ALC1 bound to such an asymmetric nucleosome indicates preferential engagement on one side. Using single-molecule FRET, we demonstrate that this asymmetric recruitment gives rise to directed sliding away from the DNA linker closest to the ADP-ribosylation site. Our data suggest a mechanism by which ALC1 slides nucleosomes away from a DNA break to render it more accessible to repair factors., Authors in the list of papers of Luka Bacic's thesis: Bacic, L., Gaullier, G., Mohapatra, J., Sabantsev, A., Mao, G., Liszczak, G., & Deindl, S.

The chromatin remodeler ALC1 is activated by DNA damage-induced poly(ADP-ribose) deposited by PARP1/PARP2 and their co-factor HPF1. ALC1 has emerged as a cancer drug target, but how it is recruited to ADP-ribosylated nucleosomes to affect their positioning near DNA breaks is unknown. Here we find that PARP1/HPF1 preferentially initiates ADP-ribosylation on the histone H2B tail closest to the DNA break. To dissect the consequences of such asymmetry, we generate nucleosomes with a defined ADP-ribosylated H2B tail on one side only. The cryo-electron microscopy structure of ALC1 bound to such an asymmetric nucleosome indicates preferential engagement on one side. Using single-molecule FRET, we demonstrate that this asymmetric recruitment gives rise to directed sliding away from the DNA linker closest to the ADP-ribosylation site. Our data suggest a mechanism by which ALC1 slides nucleosomes away from a DNA break to render it more accessible to repair factors., Authors in the list of papers of Luka Bacic's thesis: Bacic, L., Gaullier, G., Mohapatra, J., Sabantsev, A., Mao, G., Liszczak, G., & Deindl, S.

The chromatin remodeler ALC1 is activated by DNA damage-induced poly(ADP-ribose) deposited by PARP1/PARP2 and their co-factor HPF1. ALC1 has emerged as a cancer drug target, but how it is recruited to ADP-ribosylated nucleosomes to affect their positioning near DNA breaks is unknown. Here we find that PARP1/HPF1 preferentially initiates ADP-ribosylation on the histone H2B tail closest to the DNA break. To dissect the consequences of such asymmetry, we generate nucleosomes with a defined ADP-ribosylated H2B tail on one side only. The cryo-electron microscopy structure of ALC1 bound to such an asymmetric nucleosome indicates preferential engagement on one side. Using single-molecule FRET, we demonstrate that this asymmetric recruitment gives rise to directed sliding away from the DNA linker closest to the ADP-ribosylation site. Our data suggest a mechanism by which ALC1 slides nucleosomes away from a DNA break to render it more accessible to repair factors., Authors in the list of papers of Luka Bacic's thesis: Bacic, L., Gaullier, G., Mohapatra, J., Sabantsev, A., Mao, G., Liszczak, G., & Deindl, S.

The chromatin remodeler ALC1 is activated by DNA damage-induced poly(ADP-ribose) deposited by PARP1/PARP2 and their co-factor HPF1. ALC1 has emerged as a cancer drug target, but how it is recruited to ADP-ribosylated nucleosomes to affect their positioning near DNA breaks is unknown. Here we find that PARP1/HPF1 preferentially initiates ADP-ribosylation on the histone H2B tail closest to the DNA break. To dissect the consequences of such asymmetry, we generate nucleosomes with a defined ADP-ribosylated H2B tail on one side only. The cryo-electron microscopy structure of ALC1 bound to such an asymmetric nucleosome indicates preferential engagement on one side. Using single-molecule FRET, we demonstrate that this asymmetric recruitment gives rise to directed sliding away from the DNA linker closest to the ADP-ribosylation site. Our data suggest a mechanism by which ALC1 slides nucleosomes away from a DNA break to render it more accessible to repair factors., Authors in the list of papers of Luka Bacic's thesis: Bacic, L., Gaullier, G., Mohapatra, J., Sabantsev, A., Mao, G., Liszczak, G., & Deindl, S.

In contrast to humans, zebrafish have a remarkable ability to regenerate their hearts after injury, while both humans and zebrafish efficiently repair the wounded skeletal muscle. Common players in these two processes might represent potential targets for the development of efficient therapies to stimulate human heart to regenerate after injury. We identified ankrd1a expression to be upregulated in both regenerating zebrafish hearts and in repairing skeletal muscle. Its mammalian homolog ANKRD1/CARP encodes a stress responsive cardiac ankyrin repeat protein involved in transcriptional regulation, sarcomere assembly and mechanosensing. Using a TgBAC(ankrd1a:EGFP) line, we showed that activation of ankrd1a in cryoinjured heart is restricted to border zone cardiomyocytes, implicating this gene in dedifferentiation and proliferation of regenerating cardiomyocytes. After stab wound injury of skeletal muscle expression of the fluorescent reporter was observed from 3 dpi, when new EGFP-positive muscle cells emerged inside the injury zone. At later time points, EGFP-positive myofibers were visible in the deeper tissue layers, concomitant with active repair of the injured tissue. In cryoinjured skeletal muscle, strong activation of ankrd1a was also observed in myofibers adjacent to the injury, and in those on uninjured side. Detection of the transgene in both newly formed myofibers that invade the wound and in the apparently uninjured tissue surrounding the injury suggests the role of ankrd1a in skeletal muscle tissue repair and adaptive processes in uninjured myofibers surrounding the injury site. Our results implicate ankrd1a in zebrafish muscle regeneration, repair and remodeling, promoting it as an attractive target for translational studies, as a player in muscle healing and as a sensor of stressed muscle.

The chromatin remodeler ALC1 is activated by DNA damage-induced poly(ADP-ribose) deposited by PARP1/PARP2 and their co-factor HPF1. ALC1 has emerged as a cancer drug target, but how it is recruited to ADP-ribosylated nucleosomes to affect their positioning near DNA breaks is unknown. Here we find that PARP1/HPF1 preferentially initiates ADP-ribosylation on the histone H2B tail closest to the DNA break. To dissect the consequences of such asymmetry, we generate nucleosomes with a defined ADP-ribosylated H2B tail on one side only. The cryo-electron microscopy structure of ALC1 bound to such an asymmetric nucleosome indicates preferential engagement on one side. Using single-molecule FRET, we demonstrate that this asymmetric recruitment gives rise to directed sliding away from the DNA linker closest to the ADP-ribosylation site. Our data suggest a mechanism by which ALC1 slides nucleosomes away from a DNA break to render it more accessible to repair factors., Authors in the list of papers of Luka Bacic's thesis: Bacic, L., Gaullier, G., Mohapatra, J., Sabantsev, A., Mao, G., Liszczak, G., & Deindl, S.

PurposeThe aim of this study is to design a method of myocardial T1 quantification in small laboratory animals and to investigate the effects of spatiotemporal regularization and the needed acquisition duration.MethodsWe propose a compressed-sensing approach to T1 quantification based on self-gated inversion-recovery radial two/three-dimensional (2D/3D) golden-angle stack-of-stars acquisition with image reconstruction performed using total-variation spatiotemporal regularization. The method was tested on a phantom and on a healthy rat, as well as on rats in a small myocardium-remodeling study.ResultsThe results showed a good match of the T1 estimates with the results obtained using the ground-truth method on a phantom and with the literature values for rats myocardium. The proposed 2D and 3D methods showed significant differences between normal and remodeling myocardium groups for acquisition lengths down to approximately 5 and 15 min, respectively.ConclusionsA new 2D and 3D method for quantification of myocardial T1 in rats was proposed. We have shown the capability of both techniques to distinguish between normal and remodeling myocardial tissue. We have shown the effects of image-reconstruction regularization weights and acquisition length on the T1 estimates.

Background: Wall stress of the abdominal aorta (AA) appears to be an important factor in the assessment of risk for rupture based on the relationship between blood pressure and aortic diameter. We therefore investigated peak wall stress as well as isotropic and anisotropic wall stress of AA.Methods: Thirty healthy adults (male = 15) were included. Pulsatile diameter changes were determined non-invasively by an echo-tracking system, and intra-aortic pressure was measured simultaneously. A computer based mechanical model was used to compute the isotropic and anisotropic components of circumferential and longitudinal stresses.Results: Elderly males had higher total wall stress and a higher isotropic stress component in the circumferential direction and higher total longitudinal wall stress than elderly females. The isotropic component increased with age in males but not in females, whereas the anisotropic component decreased with age in both sexes.Conclusion: We found that isotropic and anisotropic properties of the abdominal aortic wall differ between young and elderly participants and between the sexes. A possible explanation could relate to chemical alterations (e.g., due to sex hormones) and changes over time in the physical distribution of fibers. Modeling of wall stress components of the human AA may contribute to a better understanding of elastin-collagen interactions during remodeling of the aortic wall., Funding: Region OEstergoetland [ROE-965959]; Medical Faculty Linkoeping University; Swedish Research Council [12,661]; Swedish Heart-Lung Foundation

Background: Wall stress of the abdominal aorta (AA) appears to be an important factor in the assessment of risk for rupture based on the relationship between blood pressure and aortic diameter. We therefore investigated peak wall stress as well as isotropic and anisotropic wall stress of AA.Methods: Thirty healthy adults (male = 15) were included. Pulsatile diameter changes were determined non-invasively by an echo-tracking system, and intra-aortic pressure was measured simultaneously. A computer based mechanical model was used to compute the isotropic and anisotropic components of circumferential and longitudinal stresses.Results: Elderly males had higher total wall stress and a higher isotropic stress component in the circumferential direction and higher total longitudinal wall stress than elderly females. The isotropic component increased with age in males but not in females, whereas the anisotropic component decreased with age in both sexes.Conclusion: We found that isotropic and anisotropic properties of the abdominal aortic wall differ between young and elderly participants and between the sexes. A possible explanation could relate to chemical alterations (e.g., due to sex hormones) and changes over time in the physical distribution of fibers. Modeling of wall stress components of the human AA may contribute to a better understanding of elastin-collagen interactions during remodeling of the aortic wall., Funding: Region OEstergoetland [ROE-965959]; Medical Faculty Linkoeping University; Swedish Research Council [12,661]; Swedish Heart-Lung Foundation

Background: Wall stress of the abdominal aorta (AA) appears to be an important factor in the assessment of risk for rupture based on the relationship between blood pressure and aortic diameter. We therefore investigated peak wall stress as well as isotropic and anisotropic wall stress of AA.Methods: Thirty healthy adults (male = 15) were included. Pulsatile diameter changes were determined non-invasively by an echo-tracking system, and intra-aortic pressure was measured simultaneously. A computer based mechanical model was used to compute the isotropic and anisotropic components of circumferential and longitudinal stresses.Results: Elderly males had higher total wall stress and a higher isotropic stress component in the circumferential direction and higher total longitudinal wall stress than elderly females. The isotropic component increased with age in males but not in females, whereas the anisotropic component decreased with age in both sexes.Conclusion: We found that isotropic and anisotropic properties of the abdominal aortic wall differ between young and elderly participants and between the sexes. A possible explanation could relate to chemical alterations (e.g., due to sex hormones) and changes over time in the physical distribution of fibers. Modeling of wall stress components of the human AA may contribute to a better understanding of elastin-collagen interactions during remodeling of the aortic wall., Funding: Region OEstergoetland [ROE-965959]; Medical Faculty Linkoeping University; Swedish Research Council [12,661]; Swedish Heart-Lung Foundation

The growing need for renovations is one of the key challenges within the Swedish multifamily rental stock. Sustainable development is essential and renovations affect all three major categories of sustainability, the social, economic and ecological factors. All buildings need to be remodeled sooner or later – the question is only when and how. With this in mind it is important to understand how renovations affect tenants’ will or wish to relocate. To succeed in dealing with the challenges revolving around these renovations, there is a need for broad and well-researched knowledge on the subject. The aim of this study is to investigate to what extent residents move out of their homes when they are affected by a renovation project. This is done by comparing renovated and unrenovated buildings located within in vicinity of each other. The study is based on data from all renovation projects within the multifamily residential stock during 2010-2022. This data includes building specific information such as size, rent increases, median income and ownership details. To map and compare relocations in relationship to renovation projects the following research questions have been studied: • How do relocation patterns differ between renovated and unrenovated buildings for comparable buildings within the same vicinity? • How do the differences in shares for relocations within renovated and unrenovated buildings compare, considering median income and rent increases, among buildings located in the same area? • Is it possible to observe a difference in relocation patterns between public and private rental multifamily residential buildings, in relation to renovations? The result from this study indicates a strong connection between larger renovations projects and the number of relocations. A larger percentage of the tenants move from the renovation projects, in comparison to its neighboring, unrenovated buildings. Moreover, the result shows that there have been relatively few large r, Sverige har ett allt mer växande renoveringsbehov. Detta till följd av att man inte har renoverat tillräckligt i kombination med att en stor del av det svenska byggnadsbeståndet uppfördes under miljonprogrammet och rekordåren. Denna utmaning kommer samtidigt som hållbarhet står högt på agendan. Renoveringar påverkar alla tre stora hållbarhetsdimensioner, ekologisk, ekonomisk och social hållbarhet. Alla byggnader behöver renoveras förr eller senare – frågan är bara när och hur. Med anledning av detta är det viktigt att förstå hur människor påverkas av renoveringar. Påverkan av renoveringar kan vara stora, det kan vara tufft att leva utan badrum och kök en period, särskilt för vissa hushåll. Vidare medför upprustningar inte sällan en ekonomisk påverkan i form av en hyreshöjning. Detta medför frågan: hur påverkas hyresgäster av renoveringar? och kanske framförallt, vad är det som får hyresgäster att flytta? Är det hyreshöjningen eller är det renoveringen i sig? Detta har under det senaste decenniet debatterats kraftigt där ordet renovräkning ofta dyker upp. Med anledning av detta studerar examensarbetet ”Flytt i samband med renovering – en kvantitativ studie av hyresbeståndet” ämnet närmare och på en större statistisk skala än tidigare. Studien ämnar jämföra hur mycket mer det flyttas i samband med renoveringar jämfört med renoveringsobjektets närmsta, orenoverade granne. Studien är en kvantitativ fallstudie av den svenska hyresbostadsmarknaden som lutar sig mot en kvalitativ litterär genomgång. Underlaget bakom de kvantitativa delarna är samtliga renoverade flerfamiljshus i Sverige mellan 2011–2021, till dessa byggnader finns deras tio närmsta orenoverade grannbyggnader. Gällande hyror i Sverige baseras dessa på bruksvärdessystemet. Kortfattat innebär det att hyran ska reflektera bostadens funktionella värde sett ur hyresgästens perspektiv. Systemet innebär att det inte går att ta ut högre hyra till följd av underhållsarbeten då exempelvis avloppets funktion ska bestå

Background Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long-term follow-up and characterization currently exist. Methods and Results Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre-transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post-transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25-1.90]; P<0.001), with similar effects in each validation cohort. This metabolite score of diastolic function was simultaneously associated with measures of multimorbidity, suggesting a metabolic link between cardiac and noncardiac state in aortic stenosis. Conclusions Metabolite profiles of cardiac structure identify individuals at high risk for death following transcatheter aortic valve implantation and concurrent multimorbidity. These results call for efforts to address potentially reversible metabolic biology associated with risk to optimize post-transcatheter aortic valve implantat

PurposeThe aim of this study is to design a method of myocardial T1 quantification in small laboratory animals and to investigate the effects of spatiotemporal regularization and the needed acquisition duration.MethodsWe propose a compressed-sensing approach to T1 quantification based on self-gated inversion-recovery radial two/three-dimensional (2D/3D) golden-angle stack-of-stars acquisition with image reconstruction performed using total-variation spatiotemporal regularization. The method was tested on a phantom and on a healthy rat, as well as on rats in a small myocardium-remodeling study.ResultsThe results showed a good match of the T1 estimates with the results obtained using the ground-truth method on a phantom and with the literature values for rats myocardium. The proposed 2D and 3D methods showed significant differences between normal and remodeling myocardium groups for acquisition lengths down to approximately 5 and 15 min, respectively.ConclusionsA new 2D and 3D method for quantification of myocardial T1 in rats was proposed. We have shown the capability of both techniques to distinguish between normal and remodeling myocardial tissue. We have shown the effects of image-reconstruction regularization weights and acquisition length on the T1 estimates.

The New Architecture of the Palace of Justice in Belgrade: Remodeling the Serbian Built Environment Towards the Spaces of Inclusivity Milica Mađanović, Institute for Philosphy and Social Theory, University of Belgrade Davor Ereš, Institute for Philosphy and Social Theory, University of Belgrade For decades, the issue of accessibility of the built environment remains one of the key topics in the societies focused on creation of equitable spaces, appropriate for use of all their citizens. The Serbian Planning and Construction Law recognizes the necessity of accessibility standards, issuing the set of accessibility norms and defining them as mandatory technical measures, standards and conditions of design, planning and construction that ensure unhindered movement and access for people with disabilities, children and the elderly. In response to the Reworking architecture/ city thematic stream, this paper aims to explore how can the remodeling of built environment, more specifically, public buildings, enhance their functionality for the people for mobility impairments. To do so, it will analyze the case study the reconstruction (arch. Z. Abadić) of the Palace of Justice in Serbia, a masterpiece originally constructed in 1973 (architects Z. Žunković and M. Živadinović). The largest judicial facility in Serbia, housing The High Court in Belgrade, the Chief Public Prosecutor's Office, the criminal department of the Second Court in Belgrade and the Second Prosecutor's Office, the Palace of Justice was fully renovated in 2019. This paper will focus on a specific aspect of the building’s remodeling approach which was least discussed in terms of architectural contemporaneity – its accessibility. The research discusses the design strategies employed to make the building accessible to the citizens with mobility impairments. The paper will answer the following questions – what was successful about the particular design decisions regarding the Palace of Justice’s accessibility, wha

The New Architecture of the Palace of Justice in Belgrade: Remodeling the Serbian Built Environment Towards the Spaces of Inclusivity Milica Mađanović, Institute for Philosphy and Social Theory, University of Belgrade Davor Ereš, Institute for Philosphy and Social Theory, University of Belgrade For decades, the issue of accessibility of the built environment remains one of the key topics in the societies focused on creation of equitable spaces, appropriate for use of all their citizens. The Serbian Planning and Construction Law recognizes the necessity of accessibility standards, issuing the set of accessibility norms and defining them as mandatory technical measures, standards and conditions of design, planning and construction that ensure unhindered movement and access for people with disabilities, children and the elderly. In response to the Reworking architecture/ city thematic stream, this paper aims to explore how can the remodeling of built environment, more specifically, public buildings, enhance their functionality for the people for mobility impairments. To do so, it will analyze the case study the reconstruction (arch. Z. Abadić) of the Palace of Justice in Serbia, a masterpiece originally constructed in 1973 (architects Z. Žunković and M. Živadinović). The largest judicial facility in Serbia, housing The High Court in Belgrade, the Chief Public Prosecutor's Office, the criminal department of the Second Court in Belgrade and the Second Prosecutor's Office, the Palace of Justice was fully renovated in 2019. This paper will focus on a specific aspect of the building’s remodeling approach which was least discussed in terms of architectural contemporaneity – its accessibility. The research discusses the design strategies employed to make the building accessible to the citizens with mobility impairments. The paper will answer the following questions – what was successful about the particular design decisions regarding the Palace of Justice’s accessibility, wha

Background: Wall stress of the abdominal aorta (AA) appears to be an important factor in the assessment of risk for rupture based on the relationship between blood pressure and aortic diameter. We therefore investigated peak wall stress as well as isotropic and anisotropic wall stress of AA.Methods: Thirty healthy adults (male = 15) were included. Pulsatile diameter changes were determined non-invasively by an echo-tracking system, and intra-aortic pressure was measured simultaneously. A computer based mechanical model was used to compute the isotropic and anisotropic components of circumferential and longitudinal stresses.Results: Elderly males had higher total wall stress and a higher isotropic stress component in the circumferential direction and higher total longitudinal wall stress than elderly females. The isotropic component increased with age in males but not in females, whereas the anisotropic component decreased with age in both sexes.Conclusion: We found that isotropic and anisotropic properties of the abdominal aortic wall differ between young and elderly participants and between the sexes. A possible explanation could relate to chemical alterations (e.g., due to sex hormones) and changes over time in the physical distribution of fibers. Modeling of wall stress components of the human AA may contribute to a better understanding of elastin-collagen interactions during remodeling of the aortic wall., Funding: Region OEstergoetland [ROE-965959]; Medical Faculty Linkoeping University; Swedish Research Council [12,661]; Swedish Heart-Lung Foundation

The growing need for renovations is one of the key challenges within the Swedish multifamily rental stock. Sustainable development is essential and renovations affect all three major categories of sustainability, the social, economic and ecological factors. All buildings need to be remodeled sooner or later – the question is only when and how. With this in mind it is important to understand how renovations affect tenants’ will or wish to relocate. To succeed in dealing with the challenges revolving around these renovations, there is a need for broad and well-researched knowledge on the subject. The aim of this study is to investigate to what extent residents move out of their homes when they are affected by a renovation project. This is done by comparing renovated and unrenovated buildings located within in vicinity of each other. The study is based on data from all renovation projects within the multifamily residential stock during 2010-2022. This data includes building specific information such as size, rent increases, median income and ownership details. To map and compare relocations in relationship to renovation projects the following research questions have been studied: • How do relocation patterns differ between renovated and unrenovated buildings for comparable buildings within the same vicinity? • How do the differences in shares for relocations within renovated and unrenovated buildings compare, considering median income and rent increases, among buildings located in the same area? • Is it possible to observe a difference in relocation patterns between public and private rental multifamily residential buildings, in relation to renovations? The result from this study indicates a strong connection between larger renovations projects and the number of relocations. A larger percentage of the tenants move from the renovation projects, in comparison to its neighboring, unrenovated buildings. Moreover, the result shows that there have been relatively few large r, Sverige har ett allt mer växande renoveringsbehov. Detta till följd av att man inte har renoverat tillräckligt i kombination med att en stor del av det svenska byggnadsbeståndet uppfördes under miljonprogrammet och rekordåren. Denna utmaning kommer samtidigt som hållbarhet står högt på agendan. Renoveringar påverkar alla tre stora hållbarhetsdimensioner, ekologisk, ekonomisk och social hållbarhet. Alla byggnader behöver renoveras förr eller senare – frågan är bara när och hur. Med anledning av detta är det viktigt att förstå hur människor påverkas av renoveringar. Påverkan av renoveringar kan vara stora, det kan vara tufft att leva utan badrum och kök en period, särskilt för vissa hushåll. Vidare medför upprustningar inte sällan en ekonomisk påverkan i form av en hyreshöjning. Detta medför frågan: hur påverkas hyresgäster av renoveringar? och kanske framförallt, vad är det som får hyresgäster att flytta? Är det hyreshöjningen eller är det renoveringen i sig? Detta har under det senaste decenniet debatterats kraftigt där ordet renovräkning ofta dyker upp. Med anledning av detta studerar examensarbetet ”Flytt i samband med renovering – en kvantitativ studie av hyresbeståndet” ämnet närmare och på en större statistisk skala än tidigare. Studien ämnar jämföra hur mycket mer det flyttas i samband med renoveringar jämfört med renoveringsobjektets närmsta, orenoverade granne. Studien är en kvantitativ fallstudie av den svenska hyresbostadsmarknaden som lutar sig mot en kvalitativ litterär genomgång. Underlaget bakom de kvantitativa delarna är samtliga renoverade flerfamiljshus i Sverige mellan 2011–2021, till dessa byggnader finns deras tio närmsta orenoverade grannbyggnader. Gällande hyror i Sverige baseras dessa på bruksvärdessystemet. Kortfattat innebär det att hyran ska reflektera bostadens funktionella värde sett ur hyresgästens perspektiv. Systemet innebär att det inte går att ta ut högre hyra till följd av underhållsarbeten då exempelvis avloppets funktion ska bestå

The aim of the present study was to further improve an in vitro 3D osteoblast (OB) – osteoclast (OC) co-culture model of bone by tuning it towards states of formation, resorption, and equilibrium for their future applications in fundamental research, drug development and personalized medicine. This was achieved by varying culture medium composition and monocyte seeding density, the two external parameters that affect cell behavior the most. Monocytes were seeded at two seeding densities onto 3D silk-fibroin constructs pre-mineralized by MSC-derived OBs and were co-cultured in one of three different media (OC stimulating, Neutral and OB stimulating medium) for three weeks. Histology showed mineralized matrix after co-culture and OC markers in the OC medium group. Scanning Electron Microscopy showed large OC-like cells in the OC medium group. Micro-computed tomography showed increased formation in the OB medium group, equilibrium in the Neutral medium group and resorption in the OC medium group. Culture supernatant samples showed high early tartrate resistant acid phosphatase (TRAP) release in the OC medium group, a later and lower release in the Neutral medium group, and almost no release in the OB medium group. Increased monocyte seeding density showed a less-than-proportional increase in TRAP release and resorption in OC medium, while it proportionally increased TRAP release in Neutral medium without affecting net resorption. The 3D OB-OC co-culture model was effectively used to show an excess of mineral deposition using OB medium, resorption using OC medium, or an equilibrium using Neutral medium. All three media applied to the model may have their own distinct applications in fundamental research, drug development, and personalized medicine.

Background: Wall stress of the abdominal aorta (AA) appears to be an important factor in the assessment of risk for rupture based on the relationship between blood pressure and aortic diameter. We therefore investigated peak wall stress as well as isotropic and anisotropic wall stress of AA.Methods: Thirty healthy adults (male = 15) were included. Pulsatile diameter changes were determined non-invasively by an echo-tracking system, and intra-aortic pressure was measured simultaneously. A computer based mechanical model was used to compute the isotropic and anisotropic components of circumferential and longitudinal stresses.Results: Elderly males had higher total wall stress and a higher isotropic stress component in the circumferential direction and higher total longitudinal wall stress than elderly females. The isotropic component increased with age in males but not in females, whereas the anisotropic component decreased with age in both sexes.Conclusion: We found that isotropic and anisotropic properties of the abdominal aortic wall differ between young and elderly participants and between the sexes. A possible explanation could relate to chemical alterations (e.g., due to sex hormones) and changes over time in the physical distribution of fibers. Modeling of wall stress components of the human AA may contribute to a better understanding of elastin-collagen interactions during remodeling of the aortic wall., Funding: Region OEstergoetland [ROE-965959]; Medical Faculty Linkoeping University; Swedish Research Council [12,661]; Swedish Heart-Lung Foundation

Cardiovascular tissue engineering is a promising approach to develop grafts that, in contrast to current replacement grafts, have the capacity to grow and remodel like native tissues. This approach largely depends on cell-driven tissue growth and remodeling, which are highly complex processes that are difficult to control inside the scaffolds used for tissue engineering. For several tissue engineering approaches, adverse tissue growth and remodeling outcomes were reported, such as aneurysm formation in vascular grafts, and leaflet retraction in heart valve grafts. It is increasingly recognized that the outcome of tissue growth and remodeling, either physiological or pathological, depends at least partly on the establishment of a homeostatic mechanical state, where one or more mechanical quantities in a tissue are maintained in equilibrium. To design long-term functioning tissue engineering strategies, understanding how scaffold parameters such as geometry affect the mechanical state of a construct, and how this state guides tissue growth and remodeling, is therefore crucial. Here, we studied how anisotropic versus isotropic mechanical loading-as imposed by initial scaffold geometry-influences tissue growth, remodeling, and the evolution of the mechanical state and geometry of tissue-engineered cardiovascular constructs in vitro. Using a custom-built bioreactor platform and nondestructive mechanical testing, we monitored the mechanical and geometric changes of elliptical and circular, vascular cell-seeded, polycaprolactone-bisurea scaffolds during 14 days of dynamic loading. The elliptical and circular scaffold geometries were designed using finite element analysis, to induce anisotropic and isotropic dynamic loading, respectively, with similar maximum stretch when cultured in the bioreactor platform. We found that the initial scaffold geometry-induced (an)isotropic loading of the engineered constructs differentially dictated the evolution of their mechanical st

Cardiovascular tissue engineering is a promising approach to develop grafts that, in contrast to current replacement grafts, have the capacity to grow and remodel like native tissues. This approach largely depends on cell-driven tissue growth and remodeling, which are highly complex processes that are difficult to control inside the scaffolds used for tissue engineering. For several tissue engineering approaches, adverse tissue growth and remodeling outcomes were reported, such as aneurysm formation in vascular grafts, and leaflet retraction in heart valve grafts. It is increasingly recognized that the outcome of tissue growth and remodeling, either physiological or pathological, depends at least partly on the establishment of a homeostatic mechanical state, where one or more mechanical quantities in a tissue are maintained in equilibrium. To design long-term functioning tissue engineering strategies, understanding how scaffold parameters such as geometry affect the mechanical state of a construct, and how this state guides tissue growth and remodeling, is therefore crucial. Here, we studied how anisotropic versus isotropic mechanical loading-as imposed by initial scaffold geometry-influences tissue growth, remodeling, and the evolution of the mechanical state and geometry of tissue-engineered cardiovascular constructs in vitro. Using a custom-built bioreactor platform and nondestructive mechanical testing, we monitored the mechanical and geometric changes of elliptical and circular, vascular cell-seeded, polycaprolactone-bisurea scaffolds during 14 days of dynamic loading. The elliptical and circular scaffold geometries were designed using finite element analysis, to induce anisotropic and isotropic dynamic loading, respectively, with similar maximum stretch when cultured in the bioreactor platform. We found that the initial scaffold geometry-induced (an)isotropic loading of the engineered constructs differentially dictated the evolution of their mechanical stat

Severe mitral regurgitation (MR) is a common valve disease which is associated with high mortality, if only managed medically. MR produces chronic and progressive volume overload with left atrial (LA) and left ventricular (LV) dilatation and dysfunction, atrial fibrillation (AF) and eventually myocardial fibrosis, irrespective of ejection fraction (EF). Surgical correction (mitral valve repair) of MR removes the volume overload, hence unmasks pre-operative LV structure and function disturbances, including reduced EF and global longitudinal and circumferential strain, as well as LA volume and strain. This review aims at describing LA remodeling before and after surgical repair.

Packaging DNA into chromatin represses essential DNA-based processes, such as transcription, DNA replication, and repair. To change the accessibility of DNA, cells have evolved a set of enzymes referred to as chromatin remodelers that act on the basic repeat unit of chromatin, the nucleosome. Chromatin remodelers are critical for normal cell physiology and development. Dysfunction or aberrant regulation of chromatin remodelers can lead to multisystem developmental disorders and cancers. DNA damage represents a major threat to eukaryotic cells. When DNA damage persists, the cell can enter programmed cell death. To avoid such a dramatic outcome, cells must rapidly recognize the DNA damage and trigger DNA repair pathways. An early event following DNA damage is the relaxation of chromatin. Chromatin relaxation depends on ATP consumption and ADP-ribosylation, where the site of DNA damage is marked with ADP-ribose units. ADP-ribose, in turn, can be recognized by the macro domain of the remodeler ALC1 (Amplified in Liver Cancer 1). ALC1 has therefore been implicated in the DNA damage response. In the absence of DNA damage, the macro domain of ALC1 is placed against its ATPase motor to inhibit its activity. However, it is unclear how ALC1, in its active state, engages the nucleosome. Moreover, the mechanism by which ALC1 is fully activated upon recruitment is poorly understood, and the impact of ALC1-catalyzed nucleosome sliding in the vicinity of a DNA damage site is unknown. This thesis investigates how ALC1 engages its substrate, the nucleosome, and how histone modifications can regulate ALC1 activity. Structural and biophysical approaches revealed an ALC1 regulatory segment that binds to the acidic patch, a prominent feature on the nucleosome surface. Further analysis showed that the interaction between ALC1 and the acidic patch is required to fully activate ALC1. Moreover, in vitro ADP-ribosylation of nucleosomes enabled us to form a stable complex of nucleosome-bound

Packaging DNA into chromatin represses essential DNA-based processes, such as transcription, DNA replication, and repair. To change the accessibility of DNA, cells have evolved a set of enzymes referred to as chromatin remodelers that act on the basic repeat unit of chromatin, the nucleosome. Chromatin remodelers are critical for normal cell physiology and development. Dysfunction or aberrant regulation of chromatin remodelers can lead to multisystem developmental disorders and cancers. DNA damage represents a major threat to eukaryotic cells. When DNA damage persists, the cell can enter programmed cell death. To avoid such a dramatic outcome, cells must rapidly recognize the DNA damage and trigger DNA repair pathways. An early event following DNA damage is the relaxation of chromatin. Chromatin relaxation depends on ATP consumption and ADP-ribosylation, where the site of DNA damage is marked with ADP-ribose units. ADP-ribose, in turn, can be recognized by the macro domain of the remodeler ALC1 (Amplified in Liver Cancer 1). ALC1 has therefore been implicated in the DNA damage response. In the absence of DNA damage, the macro domain of ALC1 is placed against its ATPase motor to inhibit its activity. However, it is unclear how ALC1, in its active state, engages the nucleosome. Moreover, the mechanism by which ALC1 is fully activated upon recruitment is poorly understood, and the impact of ALC1-catalyzed nucleosome sliding in the vicinity of a DNA damage site is unknown. This thesis investigates how ALC1 engages its substrate, the nucleosome, and how histone modifications can regulate ALC1 activity. Structural and biophysical approaches revealed an ALC1 regulatory segment that binds to the acidic patch, a prominent feature on the nucleosome surface. Further analysis showed that the interaction between ALC1 and the acidic patch is required to fully activate ALC1. Moreover, in vitro ADP-ribosylation of nucleosomes enabled us to form a stable complex of nucleosome-bound

Packaging DNA into chromatin represses essential DNA-based processes, such as transcription, DNA replication, and repair. To change the accessibility of DNA, cells have evolved a set of enzymes referred to as chromatin remodelers that act on the basic repeat unit of chromatin, the nucleosome. Chromatin remodelers are critical for normal cell physiology and development. Dysfunction or aberrant regulation of chromatin remodelers can lead to multisystem developmental disorders and cancers. DNA damage represents a major threat to eukaryotic cells. When DNA damage persists, the cell can enter programmed cell death. To avoid such a dramatic outcome, cells must rapidly recognize the DNA damage and trigger DNA repair pathways. An early event following DNA damage is the relaxation of chromatin. Chromatin relaxation depends on ATP consumption and ADP-ribosylation, where the site of DNA damage is marked with ADP-ribose units. ADP-ribose, in turn, can be recognized by the macro domain of the remodeler ALC1 (Amplified in Liver Cancer 1). ALC1 has therefore been implicated in the DNA damage response. In the absence of DNA damage, the macro domain of ALC1 is placed against its ATPase motor to inhibit its activity. However, it is unclear how ALC1, in its active state, engages the nucleosome. Moreover, the mechanism by which ALC1 is fully activated upon recruitment is poorly understood, and the impact of ALC1-catalyzed nucleosome sliding in the vicinity of a DNA damage site is unknown. This thesis investigates how ALC1 engages its substrate, the nucleosome, and how histone modifications can regulate ALC1 activity. Structural and biophysical approaches revealed an ALC1 regulatory segment that binds to the acidic patch, a prominent feature on the nucleosome surface. Further analysis showed that the interaction between ALC1 and the acidic patch is required to fully activate ALC1. Moreover, in vitro ADP-ribosylation of nucleosomes enabled us to form a stable complex of nucleosome-bound

Bone is a mineralized and elastic connective tissue that provides fundamental functions in the human body, including mechanical support to the muscles and joints, protection of vital organs and storage of minerals. Bone is a metabolically active organ that undergoes continuous remodeling processes to maintain its architecture, shape, and function throughout life. One of the most important medical discoveries of recent decades has been that the immune system is involved in bone remodeling. Indeed, chronic inflammation has been recognized as the most significant factor influencing bone homeostasis, causing a shift in the bone remodeling process toward pathological bone resorption. Bone osteolytic diseases typified by excessive bone resorption account for one of the greatest causes of disability worldwide, with significant economic and public health burdens. From this perspective, we discuss the recent findings and discoveries highlighting the cellular and molecular mechanisms that regulate this process in the bone microenvironment, in addition to the current therapeutic strategies for the treatment of osteolytic bone diseases.

Background: Wall stiffness of the abdominal aorta is an important factor in the cardiovascular risk assessment. We investigated abdominal aortic wall stiffness divided in direct and cross‑coupled stiffness components with respect to sex and age.Methods: Thirty healthy adult males (n = 15) and females were recruited and divided into three age groups: young, middle aged and elderly. Pulsatile diameter changes were determined noninvasively by an echo‑tracking system, and intra‑aortic pressure was measured simultaneously. A mechanical model was used to compute stress and stiffness in circumferential and longitudinal directions.Results: Circumferential stretch had a higher impact on longitudinal wall stress than longitudinal stretch had on circumferential wall stress. Furthermore, there were an age‑related and sex‑independent increase in circumferential and longitudinal direct and cross‑coupled stiffnesses and a decrease in circumferential and longitudinal stretch of the abdominal aortic wall. For the young group, females had a stiffer wall compared to males, while the male aortic wall grew stiffer with age at a higher rate, reaching a similar level to that of the females in the elderly group.Conclusion: Temporal changes in aortic stiffness suggest an age‑related change in wall constituents that is expressed in terms of circumferential remodeling impacting longitudinal stress. These mechanisms may be active in the development of aortic tortuosity. We observed an age‑dependent increase in circumferential and longitudinal stiffnesses as well as decrease in stretch. A possible mechanism related to the observed changes could act via chemi‑cal alterations of wall constituents and changes in the physical distribution of fibers. Furthermore, modeling of force distribution in the wall of the human abdominal aorta may contribute to a better understanding of elastin–collagen interactions during remodeling of the aortic wall., Funding: Linkoping University; Region Ostergotland; Medical Faculty Linkoping University; Swedish Research Council [12661]; Swedish Heart-Lung Foundation

Background: Wall stiffness of the abdominal aorta is an important factor in the cardiovascular risk assessment. We investigated abdominal aortic wall stiffness divided in direct and cross‑coupled stiffness components with respect to sex and age.Methods: Thirty healthy adult males (n = 15) and females were recruited and divided into three age groups: young, middle aged and elderly. Pulsatile diameter changes were determined noninvasively by an echo‑tracking system, and intra‑aortic pressure was measured simultaneously. A mechanical model was used to compute stress and stiffness in circumferential and longitudinal directions.Results: Circumferential stretch had a higher impact on longitudinal wall stress than longitudinal stretch had on circumferential wall stress. Furthermore, there were an age‑related and sex‑independent increase in circumferential and longitudinal direct and cross‑coupled stiffnesses and a decrease in circumferential and longitudinal stretch of the abdominal aortic wall. For the young group, females had a stiffer wall compared to males, while the male aortic wall grew stiffer with age at a higher rate, reaching a similar level to that of the females in the elderly group.Conclusion: Temporal changes in aortic stiffness suggest an age‑related change in wall constituents that is expressed in terms of circumferential remodeling impacting longitudinal stress. These mechanisms may be active in the development of aortic tortuosity. We observed an age‑dependent increase in circumferential and longitudinal stiffnesses as well as decrease in stretch. A possible mechanism related to the observed changes could act via chemi‑cal alterations of wall constituents and changes in the physical distribution of fibers. Furthermore, modeling of force distribution in the wall of the human abdominal aorta may contribute to a better understanding of elastin–collagen interactions during remodeling of the aortic wall., Funding: Linkoping University; Region Ostergotland; Medical Faculty Linkoping University; Swedish Research Council [12661]; Swedish Heart-Lung Foundation

ObjectiveThe Ross procedure is an excellent option for children or young adults who need aortic valve replacement because it can restore survival to that of the normal aged-matched population. However, autograft remodeling can lead to aneurysmal formation and reoperation, and the biomechanics of this process is unknown. This study investigated postoperative autograft remodeling after the Ross procedure by examining patient-specific autograft wall stresses.MethodsPatients who have undergone the Ross procedure who had intraoperative pulmonary root and aortic specimens collected were recruited. Patient-specific models (n = 16) were developed using patient-specific material property and their corresponding geometry from cine magnetic resonance imaging at 1-year follow-up. Autograft ± Dacron for aneurysm repair and ascending aortic geometries were reconstructed to develop patient-specific finite element models, which incorporated material properties and wall thickness experimentally measured from biaxial stretching. A multiplicative approach was used to account for prestress geometry from in vivo magnetic resonance imaging. Pressure loading to systemic pressure (120/80) was performed using LS-DYNA software (LSTC Inc, Livermore, Calif).ResultsAt systole, first principal stresses were 809 kPa (25%-75% interquartile range, 691-1219 kPa), 567 kPa (485-675 kPa), 637 kPa (555-755 kPa), and 382 kPa (334-413 kPa) at the autograft sinotubular junction, sinuses, annulus, and ascending aorta, respectively. Second principal stresses were 360 kPa (310-426 kPa), 355 kPa (320-394 kPa), 272 kPa (252-319 kPa), and 184 kPa (147-222 kPa) at the autograft sinotubular junction, sinuses, annulus, and ascending aorta, respectively. Mean autograft diameters were 29.9 ± 2.7 mm, 38.3 ± 5.3 mm, and 26.6 ± 4.0 mm at the sinotubular junction, sinu

As one of the two highly conserved cellular degradation systems, autophagy plays a critical role in regulation of protein, lipid, and organelle quality control and cellular homeostasis. This evolutionarily conserved pathway singles out intracellular substrates for elimination via encapsulation within a double-membrane vesicle and delivery to the lysosome for degradation. Multiple cancers disrupt normal regulation of autophagy and hijack its degradative ability to remodel their proteome, reprogram their metabolism, and adapt to environmental challenges, making the autophagy-lysosome system a prime target for anti-cancer interventions. Here, we discuss the roles of autophagy in tumor progression, including cancer-specific mechanisms of autophagy regulation and the contribution of tumor and host autophagy in metabolic regulation, immune evasion, and malignancy. We further discuss emerging proteomics-based approaches for systematic profiling of autophagosome-lysosome composition and contents. Together, these approaches are uncovering new features and functions of autophagy, leading to more effective strategies for targeting this pathway in cancer.

Background: Wall stiffness of the abdominal aorta is an important factor in the cardiovascular risk assessment. We investigated abdominal aortic wall stiffness divided in direct and cross‑coupled stiffness components with respect to sex and age.Methods: Thirty healthy adult males (n = 15) and females were recruited and divided into three age groups: young, middle aged and elderly. Pulsatile diameter changes were determined noninvasively by an echo‑tracking system, and intra‑aortic pressure was measured simultaneously. A mechanical model was used to compute stress and stiffness in circumferential and longitudinal directions.Results: Circumferential stretch had a higher impact on longitudinal wall stress than longitudinal stretch had on circumferential wall stress. Furthermore, there were an age‑related and sex‑independent increase in circumferential and longitudinal direct and cross‑coupled stiffnesses and a decrease in circumferential and longitudinal stretch of the abdominal aortic wall. For the young group, females had a stiffer wall compared to males, while the male aortic wall grew stiffer with age at a higher rate, reaching a similar level to that of the females in the elderly group.Conclusion: Temporal changes in aortic stiffness suggest an age‑related change in wall constituents that is expressed in terms of circumferential remodeling impacting longitudinal stress. These mechanisms may be active in the development of aortic tortuosity. We observed an age‑dependent increase in circumferential and longitudinal stiffnesses as well as decrease in stretch. A possible mechanism related to the observed changes could act via chemi‑cal alterations of wall constituents and changes in the physical distribution of fibers. Furthermore, modeling of force distribution in the wall of the human abdominal aorta may contribute to a better understanding of elastin–collagen interactions during remodeling of the aortic wall., Funding: Linkoping University; Region Ostergotland; Medical Faculty Linkoping University; Swedish Research Council [12661]; Swedish Heart-Lung Foundation

Background: Wall stiffness of the abdominal aorta is an important factor in the cardiovascular risk assessment. We investigated abdominal aortic wall stiffness divided in direct and cross‑coupled stiffness components with respect to sex and age.Methods: Thirty healthy adult males (n = 15) and females were recruited and divided into three age groups: young, middle aged and elderly. Pulsatile diameter changes were determined noninvasively by an echo‑tracking system, and intra‑aortic pressure was measured simultaneously. A mechanical model was used to compute stress and stiffness in circumferential and longitudinal directions.Results: Circumferential stretch had a higher impact on longitudinal wall stress than longitudinal stretch had on circumferential wall stress. Furthermore, there were an age‑related and sex‑independent increase in circumferential and longitudinal direct and cross‑coupled stiffnesses and a decrease in circumferential and longitudinal stretch of the abdominal aortic wall. For the young group, females had a stiffer wall compared to males, while the male aortic wall grew stiffer with age at a higher rate, reaching a similar level to that of the females in the elderly group.Conclusion: Temporal changes in aortic stiffness suggest an age‑related change in wall constituents that is expressed in terms of circumferential remodeling impacting longitudinal stress. These mechanisms may be active in the development of aortic tortuosity. We observed an age‑dependent increase in circumferential and longitudinal stiffnesses as well as decrease in stretch. A possible mechanism related to the observed changes could act via chemi‑cal alterations of wall constituents and changes in the physical distribution of fibers. Furthermore, modeling of force distribution in the wall of the human abdominal aorta may contribute to a better understanding of elastin–collagen interactions during remodeling of the aortic wall., Funding: Linkoping University; Region Ostergotland; Medical Faculty Linkoping University; Swedish Research Council [12661]; Swedish Heart-Lung Foundation

Bone is a mineralized and elastic connective tissue that provides fundamental functions in the human body, including mechanical support to the muscles and joints, protection of vital organs and storage of minerals. Bone is a metabolically active organ that undergoes continuous remodeling processes to maintain its architecture, shape, and function throughout life. One of the most important medical discoveries of recent decades has been that the immune system is involved in bone remodeling. Indeed, chronic inflammation has been recognized as the most significant factor influencing bone homeostasis, causing a shift in the bone remodeling process toward pathological bone resorption. Bone osteolytic diseases typified by excessive bone resorption account for one of the greatest causes of disability worldwide, with significant economic and public health burdens. From this perspective, we discuss the recent findings and discoveries highlighting the cellular and molecular mechanisms that regulate this process in the bone microenvironment, in addition to the current therapeutic strategies for the treatment of osteolytic bone diseases.

Background: Wall stiffness of the abdominal aorta is an important factor in the cardiovascular risk assessment. We investigated abdominal aortic wall stiffness divided in direct and cross‑coupled stiffness components with respect to sex and age.Methods: Thirty healthy adult males (n = 15) and females were recruited and divided into three age groups: young, middle aged and elderly. Pulsatile diameter changes were determined noninvasively by an echo‑tracking system, and intra‑aortic pressure was measured simultaneously. A mechanical model was used to compute stress and stiffness in circumferential and longitudinal directions.Results: Circumferential stretch had a higher impact on longitudinal wall stress than longitudinal stretch had on circumferential wall stress. Furthermore, there were an age‑related and sex‑independent increase in circumferential and longitudinal direct and cross‑coupled stiffnesses and a decrease in circumferential and longitudinal stretch of the abdominal aortic wall. For the young group, females had a stiffer wall compared to males, while the male aortic wall grew stiffer with age at a higher rate, reaching a similar level to that of the females in the elderly group.Conclusion: Temporal changes in aortic stiffness suggest an age‑related change in wall constituents that is expressed in terms of circumferential remodeling impacting longitudinal stress. These mechanisms may be active in the development of aortic tortuosity. We observed an age‑dependent increase in circumferential and longitudinal stiffnesses as well as decrease in stretch. A possible mechanism related to the observed changes could act via chemi‑cal alterations of wall constituents and changes in the physical distribution of fibers. Furthermore, modeling of force distribution in the wall of the human abdominal aorta may contribute to a better understanding of elastin–collagen interactions during remodeling of the aortic wall., Funding: Linkoping University; Region Ostergotland; Medical Faculty Linkoping University; Swedish Research Council [12661]; Swedish Heart-Lung Foundation

Packaging DNA into chromatin represses essential DNA-based processes, such as transcription, DNA replication, and repair. To change the accessibility of DNA, cells have evolved a set of enzymes referred to as chromatin remodelers that act on the basic repeat unit of chromatin, the nucleosome. Chromatin remodelers are critical for normal cell physiology and development. Dysfunction or aberrant regulation of chromatin remodelers can lead to multisystem developmental disorders and cancers. DNA damage represents a major threat to eukaryotic cells. When DNA damage persists, the cell can enter programmed cell death. To avoid such a dramatic outcome, cells must rapidly recognize the DNA damage and trigger DNA repair pathways. An early event following DNA damage is the relaxation of chromatin. Chromatin relaxation depends on ATP consumption and ADP-ribosylation, where the site of DNA damage is marked with ADP-ribose units. ADP-ribose, in turn, can be recognized by the macro domain of the remodeler ALC1 (Amplified in Liver Cancer 1). ALC1 has therefore been implicated in the DNA damage response. In the absence of DNA damage, the macro domain of ALC1 is placed against its ATPase motor to inhibit its activity. However, it is unclear how ALC1, in its active state, engages the nucleosome. Moreover, the mechanism by which ALC1 is fully activated upon recruitment is poorly understood, and the impact of ALC1-catalyzed nucleosome sliding in the vicinity of a DNA damage site is unknown. This thesis investigates how ALC1 engages its substrate, the nucleosome, and how histone modifications can regulate ALC1 activity. Structural and biophysical approaches revealed an ALC1 regulatory segment that binds to the acidic patch, a prominent feature on the nucleosome surface. Further analysis showed that the interaction between ALC1 and the acidic patch is required to fully activate ALC1. Moreover, in vitro ADP-ribosylation of nucleosomes enabled us to form a stable complex of nucleosome-bound

Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling.

Cardiovascular tissue engineering is a promising approach to develop grafts that, in contrast to current replacement grafts, have the capacity to grow and remodel like native tissues. This approach largely depends on cell-driven tissue growth and remodeling, which are highly complex processes that are difficult to control inside the scaffolds used for tissue engineering. For several tissue engineering approaches, adverse tissue growth and remodeling outcomes were reported, such as aneurysm formation in vascular grafts, and leaflet retraction in heart valve grafts. It is increasingly recognized that the outcome of tissue growth and remodeling, either physiological or pathological, depends at least partly on the establishment of a homeostatic mechanical state, where one or more mechanical quantities in a tissue are maintained in equilibrium. To design long-term functioning tissue engineering strategies, understanding how scaffold parameters such as geometry affect the mechanical state of a construct, and how this state guides tissue growth and remodeling, is therefore crucial. Here, we studied how anisotropic versus isotropic mechanical loading-as imposed by initial scaffold geometry-influences tissue growth, remodeling, and the evolution of the mechanical state and geometry of tissue-engineered cardiovascular constructs in vitro. Using a custom-built bioreactor platform and nondestructive mechanical testing, we monitored the mechanical and geometric changes of elliptical and circular, vascular cell-seeded, polycaprolactone-bisurea scaffolds during 14 days of dynamic loading. The elliptical and circular scaffold geometries were designed using finite element analysis, to induce anisotropic and isotropic dynamic loading, respectively, with similar maximum stretch when cultured in the bioreactor platform. We found that the initial scaffold geometry-induced (an)isotropic loading of the engineered constructs differentially dictated the evolution of their mechanical stat

Packaging DNA into chromatin represses essential DNA-based processes, such as transcription, DNA replication, and repair. To change the accessibility of DNA, cells have evolved a set of enzymes referred to as chromatin remodelers that act on the basic repeat unit of chromatin, the nucleosome. Chromatin remodelers are critical for normal cell physiology and development. Dysfunction or aberrant regulation of chromatin remodelers can lead to multisystem developmental disorders and cancers. DNA damage represents a major threat to eukaryotic cells. When DNA damage persists, the cell can enter programmed cell death. To avoid such a dramatic outcome, cells must rapidly recognize the DNA damage and trigger DNA repair pathways. An early event following DNA damage is the relaxation of chromatin. Chromatin relaxation depends on ATP consumption and ADP-ribosylation, where the site of DNA damage is marked with ADP-ribose units. ADP-ribose, in turn, can be recognized by the macro domain of the remodeler ALC1 (Amplified in Liver Cancer 1). ALC1 has therefore been implicated in the DNA damage response. In the absence of DNA damage, the macro domain of ALC1 is placed against its ATPase motor to inhibit its activity. However, it is unclear how ALC1, in its active state, engages the nucleosome. Moreover, the mechanism by which ALC1 is fully activated upon recruitment is poorly understood, and the impact of ALC1-catalyzed nucleosome sliding in the vicinity of a DNA damage site is unknown. This thesis investigates how ALC1 engages its substrate, the nucleosome, and how histone modifications can regulate ALC1 activity. Structural and biophysical approaches revealed an ALC1 regulatory segment that binds to the acidic patch, a prominent feature on the nucleosome surface. Further analysis showed that the interaction between ALC1 and the acidic patch is required to fully activate ALC1. Moreover, in vitro ADP-ribosylation of nucleosomes enabled us to form a stable complex of nucleosome-bound

Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling.

Most functional biopharmaceuticals such as antibodies are glycoproteins carrying N-linked oligosaccharides (N-glycans). In animal cells, these glycans are generally expressed as heterogeneous glycoforms that are difficult to separate into a pure form. The structure of these glycans directly affects several biological aspects of the glycoproteins, especially binding affinity. Therefore, the preparation of glycoproteins with well-defined and homogeneous glycoforms is necessary for functional studies and improved efficacy, particularly for biopharmaceuticals. This review describes the recent remarkable progress in the development and production of biopharmaceutical glycan-modified antibodies, through the use of glycan remodeling using microbial endoglycosidases and sophisticated glycoengineering techniques utilizing microbial enzymatic reaction mechanisms.

Background: Allergic asthma (AA) is a complex disorder with heterogeneous features of airway hyperresponsiveness, inflammation, and remodeling. The increase of airway smooth muscle (ASM) mass is a fundamental component of bronchial remodeling in AA, yet the pathophysiological mechanisms and clinical outcomes associated with ASM modulation are still elusive. Objective: To compare the expression level of β-dystroglycan (β-DG) in ASM in AA subjects and a healthy control group and to investigate the relationship between eosinophils and β-DG in ASM in patients with AA. Methods: Thirteen AA patients and seven control subjects were analyzed for the ASM area and eosinophil cells. Bronchial biopsies were stained by β-DG and eosinophil cationic protein (ECP) using immunohistochemistry. Results: The proportion of ASM with β-DG staining was greater in those with AA than in the healthy control group (mean (95% CI) (28.3% (23.8–32.7%) vs. 16.4% (14.1–18.5%), P < 0.0001). The number of ECP–positive cells was higher in patients with AA than in the control group (4,056 (3,819–4,296) vs. 466 (395–537) cells/mm2 P < 0.0001). In AA, the number of ECP positive cells was significantly correlated to the β-DG expression in ASM (r = 0.77, P = 0.002). Conclusion: There is an increased β-DG expression in ASM and a higher number of ECP positive cells in the bronchial biopsy of those with AA than those in the control group. The increased expression of β-DG in ASM in AA subjects correlates with the number of eosinophils, suggesting a role for this cell in airway remodeling in AA.

Pulmonary arterial hypertension (PAH) is a disease resulting in increased right ventricular (RV) afterload and RV remodeling. PAH results in altered RV structure and function at different scales from organ-level hemodynamics to tissue-level biomechanical properties, fiber-level architecture, and cardiomyocyte-level contractility. Biomechanical analysis of RV pathophysiology has drawn significant attention over the past years and recent work has found a close link between RV biomechanics and physiological function. Building upon previously developed techniques, biomechanical studies have employed multi-scale analysis frameworks to investigate the underlying mechanisms of RV remodeling in PAH and effects of potential therapeutic interventions on these mechanisms. In this review, we discuss the current understanding of RV structure and function in PAH, highlighting the findings from recent studies on the biomechanics of RV remodeling at organ, tissue, fiber, and cellular levels. Recent progress in understanding the underlying mechanisms of RV remodeling in PAH, and effects of potential therapeutics, will be highlighted from a biomechanical perspective. The clinical relevance of RV biomechanics in PAH will be discussed, followed by addressing the current knowledge gaps and providing suggested directions for future research.

Background: Allergic asthma (AA) is a complex disorder with heterogeneous features of airway hyperresponsiveness, inflammation, and remodeling. The increase of airway smooth muscle (ASM) mass is a fundamental component of bronchial remodeling in AA, yet the pathophysiological mechanisms and clinical outcomes associated with ASM modulation are still elusive. Objective: To compare the expression level of β-dystroglycan (β-DG) in ASM in AA subjects and a healthy control group and to investigate the relationship between eosinophils and β-DG in ASM in patients with AA. Methods: Thirteen AA patients and seven control subjects were analyzed for the ASM area and eosinophil cells. Bronchial biopsies were stained by β-DG and eosinophil cationic protein (ECP) using immunohistochemistry. Results: The proportion of ASM with β-DG staining was greater in those with AA than in the healthy control group (mean (95% CI) (28.3% (23.8–32.7%) vs. 16.4% (14.1–18.5%), P < 0.0001). The number of ECP–positive cells was higher in patients with AA than in the control group (4,056 (3,819–4,296) vs. 466 (395–537) cells/mm2 P < 0.0001). In AA, the number of ECP positive cells was significantly correlated to the β-DG expression in ASM (r = 0.77, P = 0.002). Conclusion: There is an increased β-DG expression in ASM and a higher number of ECP positive cells in the bronchial biopsy of those with AA than those in the control group. The increased expression of β-DG in ASM in AA subjects correlates with the number of eosinophils, suggesting a role for this cell in airway remodeling in AA.

Background: Allergic asthma (AA) is a complex disorder with heterogeneous features of airway hyperresponsiveness, inflammation, and remodeling. The increase of airway smooth muscle (ASM) mass is a fundamental component of bronchial remodeling in AA, yet the pathophysiological mechanisms and clinical outcomes associated with ASM modulation are still elusive. Objective: To compare the expression level of β-dystroglycan (β-DG) in ASM in AA subjects and a healthy control group and to investigate the relationship between eosinophils and β-DG in ASM in patients with AA. Methods: Thirteen AA patients and seven control subjects were analyzed for the ASM area and eosinophil cells. Bronchial biopsies were stained by β-DG and eosinophil cationic protein (ECP) using immunohistochemistry. Results: The proportion of ASM with β-DG staining was greater in those with AA than in the healthy control group (mean (95% CI) (28.3% (23.8–32.7%) vs. 16.4% (14.1–18.5%), P < 0.0001). The number of ECP–positive cells was higher in patients with AA than in the control group (4,056 (3,819–4,296) vs. 466 (395–537) cells/mm2 P < 0.0001). In AA, the number of ECP positive cells was significantly correlated to the β-DG expression in ASM (r = 0.77, P = 0.002). Conclusion: There is an increased β-DG expression in ASM and a higher number of ECP positive cells in the bronchial biopsy of those with AA than those in the control group. The increased expression of β-DG in ASM in AA subjects correlates with the number of eosinophils, suggesting a role for this cell in airway remodeling in AA.

Stress-fractures of bone are similar to fatigue fractures in engineering materials as both are caused by microdamage accumulation under repetitive loading. However, stress-fractures have a biologic component, since bone tissue is capable of repairing damage and/or adding mass in response to damaging loading. The cellular damage repair processes cause transient porosities to develop in bone tissue, which temporarily reduce modulus and increase the damage accumulation rate if damaging loading is continued. Consequently, the stress fracture process is an interaction between bone’s mechanical response to high-levels of loading (damage accumulation), and the biological responses of repair and hypertrophy that change tissue modulus. This work focuses on stress-reactions, bone tissue changes that precede a stress-fracture, in athletes. Specifically, racehorse proximal sesamoid bone (PSB) fracture is used as a naturally occurring model of an osteochondral stress fracture. The PSBs are a pair of bones in the metacarpophalangeal (fetlock) joint of the distal forelimb and PSB fracture is one of the most common fatal musculoskeletal injuries associated with race training. In this work, morphologic tissue properties between PSB from racehorses with (Case) and without (Control) a unilateral biaxial PSB are compared. Both Case and Control horses were in race-training at the time of death and their training histories were known. The observed tissue properties are related to exercise. In addition, a compartment model of bone’s turnover cycle is introduced and used to explain the associations among morphologic variables and exercise. The collected morphologic data is used to solve for the model’s steady-state rate constants. Finally, the relationship between PSB kinematics and how PSB motion may impact PSB fracture risk is explored. Our primary finding was that horses in higher intensity training develop a subchondral stress-reaction (lesion). A subchondral bone lesion was consistent

Physical exercise and   systemic  hypertension  are associated with cardiac adaptive mechanisms. As left ventricle is more prone to BP changes, the impact is most prominent on the left side of the heart, which leads to left ventricular remodeling and in consequence left ventricular  hypertrophy. [1]Since the sensitivity of the different ECG criteria may be as low as 7 to 35 percent with mild LVH and only 10 to 50 percent with moderate-to-severe disease, echocardiography is the diagnostic procedure of choice [2] Although it is relatively insensitive, electrocardiography (ECG) does have prognostic significance [ 3] Left ventricular hypertrophy (LVH) is a common finding in patients with fixed or borderline  hypertension.  Previous studies have already shown that exaggerated response of BP to exercise is a valid risk factor for future developing of hypertension. It often does not correlate with a grade of hypertension the objective or the article is to collect information about studies that review structural and functional cardiac changes seen in patient with High normal and Grade I hypertension.