| 1. |
- Nandadasa, Sumeda, et al.
(författare)
-
Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth
- 2020
-
Ingår i: eLife. - 2050-084X. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- The umbilical artery lumen closes rapidly at birth, preventing neonatal blood loss, whereas the umbilical vein remains patent longer. Here, analysis of umbilical cords from humans and other mammals identified differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. The umbilical artery, but not the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism revealed by biomechanical observations and confirmed by computational analyses. This vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrate their opposing roles in umbilical vascular dimorphism, including effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that differential proteoglycan dynamics and inner layer buckling were positively selected during evolution.
|
|
| 2. |
|
|
| 3. |
- Bhutada, Sumit, et al.
(författare)
-
Identification of protein biomarkers associated with congenital diaphragmatic hernia in human amniotic fluid
- 2023
-
Ingår i: Scientific Reports. - 2045-2322. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Congenital diaphragmatic hernia (CDH) is a severe birth defect frequently associated with pulmonary hypoplasia, pulmonary hypertension, and heart failure. Since amniotic fluid comprises proteins of both fetal and maternal origin, its analysis could provide insights on mechanisms underlying CDH and provide biomarkers for early diagnosis, severity of pulmonary changes and treatment response. The study objective was to identify proteomic changes in amniotic fluid consistently associated with CDH. Amniotic fluid was obtained at term (37–39 weeks) from women with normal pregnancies (n = 5) or carrying fetuses with CDH (n = 5). After immuno-depletion of the highest abundance proteins, off-line fractionation and high-resolution tandem mass spectrometry were performed and quantitative differences between the proteomes of the groups were determined. Of 1036 proteins identified, 218 were differentially abundant. Bioinformatics analysis showed significant changes in GP6 signaling, in the MSP–RON signaling in macrophages pathway and in networks associated with cardiovascular system development and function, connective tissue disorders and dermatological conditions. Differences in selected proteins, namely pulmonary surfactant protein B, osteopontin, kallikrein 5 and galectin-3 were validated by orthogonal testing using ELISA in larger cohorts and showed statistically significant differences aiding in the diagnosis and prediction of CDH. The findings provide potential tools for clinical management of CDH.
|
|
| 4. |
- Chi, Jinshu, et al.
(författare)
-
The Net Landscape Carbon Balance—Integrating terrestrial and aquatic carbon fluxes in a managed boreal forest landscape in Sweden
- 2020
-
Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 26:4, s. 2353-2367
-
Tidskriftsartikel (refereegranskat)abstract
- The boreal biome exchanges large amounts of carbon (C) and greenhouse gases (GHGs) with the atmosphere and thus significantly affects the global climate. A managed boreal landscape consists of various sinks and sources of carbon dioxide (CO2), methane (CH4), and dissolved organic and inorganic carbon (DOC and DIC) across forests, mires, lakes, and streams. Due to the spatial heterogeneity, large uncertainties exist regarding the net landscape carbon balance (NLCB). In this study, we compiled terrestrial and aquatic fluxes of CO2, CH4, DOC, DIC, and harvested C obtained from tall-tower eddy covariance measurements, stream monitoring, and remote sensing of biomass stocks for an entire boreal catchment (~68 km2) in Sweden to estimate the NLCB across the land–water–atmosphere continuum. Our results showed that this managed boreal forest landscape was a net C sink (NLCB = 39 g C m−2 year−1) with the landscape–atmosphere CO2 exchange being the dominant component, followed by the C export via harvest and streams. Accounting for the global warming potential of CH4, the landscape was a GHG sink of 237 g CO2-eq m−2 year−1, thus providing a climate-cooling effect. The CH4 flux contribution to the annual GHG budget increased from 0.6% during spring to 3.2% during winter. The aquatic C loss was most significant during spring contributing 8% to the annual NLCB. We further found that abiotic controls (e.g., air temperature and incoming radiation) regulated the temporal variability of the NLCB whereas land cover types (e.g., mire vs. forest) and management practices (e.g., clear-cutting) determined their spatial variability. Our study advocates the need for integrating terrestrial and aquatic fluxes at the landscape scale based on tall-tower eddy covariance measurements combined with biomass stock and stream monitoring to develop a holistic understanding of the NLCB of managed boreal forest landscapes and to better evaluate their potential for mitigating climate change.
|
|
| 5. |
- Ivanycheva, Diana, et al.
(författare)
-
Lifestyle entrepreneurship : Literature review and future research agenda
- 2023
-
Ingår i: Journal of Management Studies. - : John Wiley & Sons. - 0022-2380 .- 1467-6486.
-
Forskningsöversikt (refereegranskat)abstract
- Research in leading entrepreneurship and management journals has tended to conceptualize entrepreneurship as motivated by the goals of wealth, income, or social value creation. This research has thus largely overlooked entrepreneurial motivations such as the desire to engage in particular activities that the entrepreneurs find rewarding or the desire to live in particular locations. The literature on such Lifestyle Entrepreneurship (LE) includes research on artisan, artistic, craft, creative, fitness, hobbyist, leisure, sport, and tourism entrepreneurship. This literature has grown quickly over the last decade, but it is scattered across a range of domains, disciplines, and journals and lacks conceptual clarity. In this review, we take stock, synthesize and offer definitions and a framework for investigation of LE that allows for its development and theoretical integration with, and contribution to, existing entrepreneurship theory. We conceptualize LE in relation to its purpose and function, identify different types of LE, and examine their respective antecedents, behaviors, and outcomes. We propose a research agenda based on the merits of viewing LE as a distinctive and theoretically important domain for the study of entrepreneurship and highlight the vital role that LE plays in enriching both individual and social welfare.
|
|
| 6. |
- Lundmark, Fanny, et al.
(författare)
-
Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer-Optimization of the Affinity towards PSMA by Linker Modification in Murine Model
- 2020
-
Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 12:7
-
Tidskriftsartikel (refereegranskat)abstract
- Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are promising targets for molecular imaging of prostate cancer (PCa) lesions. Due to the heterogenic overexpression of PSMA and GRPR in PCa, a heterodimeric radiotracer with the ability to bind to both targets could be beneficial. Recently, our group reported the novel heterodimer BQ7800 consisting of a urea-based PSMA inhibitor, the peptide-based GRPR antagonist RM26 and NOTA chelator. The study reported herein, aimed to improve the affinity of BQ7800 towards PSMA by changing the composition of the two linkers connecting the PSMA- and GRPR-targeting motifs. Three novel heterodimeric analogues were synthesized by incorporation of phenylalanine in the functional linker of the PSMA-binding motif and/or shortening the PEG-linker coupled to RM26. The heterodimers were labeled with indium-111 and evaluated in vitro. In the competitive binding assay, BQ7812, featuring phenylalanine and shorter PEG-linker, demonstrated a nine-fold improved affinity towards PSMA. In the in vivo biodistribution study of [In-111]In-BQ7812 in PC3-pip tumor-bearing mice (PSMA and GRPR positive), the activity uptake was two-fold higher in the tumor and three-fold higher in kidneys than for [In-111]In-BQ7800. Herein, we showed that the affinity of a bispecific PSMA/GRPR heterodimer towards PSMA could be improved by linker modification.
|
|
| 7. |
- Lundmark, Fanny, et al.
(författare)
-
Preclinical Characterisation of PSMA/GRPR-Targeting Heterodimer [Ga-68]Ga-BQ7812 for PET Diagnostic Imaging of Prostate Cancer : A Step towards Clinical Translation
- 2023
-
Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:2
-
Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Prostate cancer continues to be the most frequently diagnosed form of cancer and the leading cause of cancer-related deaths among men. For a successful treatment plan and outcome, an early diagnosis, correct staging, and monitoring of treatment response are crucial. To improve this, a radiotracer could be used to target the two most abundant proteins overexpressed in prostate cancer: prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR). To date, no such heterodimeric radiotracer is used in the clinic. In this study, we have preclinically characterized and evaluated a galium-68 labelled PSMA/GRPR-targeting radiotracer for PET imaging of prostate cancer. We hope that the findings from this study will be able to contribute to designing better heterodimeric ligands, promote clinical translation of a heterodimer, and serve as a step towards a first-in-human study. The development of radioligands targeting prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) has shown promising results for the imaging and therapy of prostate cancer. However, studies have shown that tumors and metastases can express such targets heterogeneously. To overcome this issue and to improve protein binding, radioligands with the ability to bind both PSMA and GRPR have been developed. Herein, we present the preclinical characterization of [Ga-68]Ga-BQ7812; a PSMA/GRPR-targeting radioligand for the diagnostic PET imaging of prostate cancer. This study aimed to evaluate [Ga-68]Ga-BQ7812 to promote the translation of such imaging probes into the clinic. [Ga-68]Ga-BQ7812 demonstrated rapid and specific binding to both targets in a PSMA/GRPR-expressing PC3-pip cell line. Results from the biodistribution study in PC3-pip xenografted mice showed specific binding to both targets, with the highest activity uptake at 1 h pi in tumor (PSMA+/GRPR+, 10.4 +/- 1.0% IA/g), kidneys (PSMA+, 45 +/- 16% IA/g), and pancreas (GRPR+, 5.6 +/- 0.7% IA/g). At 3h pi, increased tumour-to-organ ratios could be seen due to higher retention in the tumor compared with other PSMA or GRPR-expressing organs. These results, together with low toxicity and an acceptable estimated dosimetry profile (total effective dose = 0.0083 mSv/MBq), support the clinical translation of [Ga-68]Ga-BQ7812 and represent a step towards its first clinical trial.
|
|
| 8. |
- Lundmark, Fanny, et al.
(författare)
-
Reduction of renal activity retention of radiolabeled albumin binding domain-derived affinity proteins using a non-residualizing label strategy compared with a cleavable glycine-leucine-glycine-lysine-linker
- 2024
-
Ingår i: Molecular Medicine Reports. - : Spandidos Publications. - 1791-2997 .- 1791-3004. ; 29:2
-
Tidskriftsartikel (refereegranskat)abstract
- The feasibility of targeted imaging and therapy using radiolabeled albumin-binding domain-derived affinity proteins (ADAPTs) has been demonstrated. However, high renal uptake of radioactivity limits the maximum tolerated dose. Successful reduction of renal retention of radiolabeled Fab fragments has been demonstrated by incorporating a cleavable linker between the targeting agent and the radiometal chelator. The present study investigated if the introduction of a glycine-leucine-glycine-lysine (GLGK)-linker would reduce the kidney uptake of radiolabeled ADAPT6 and also compared it with the non-residualizing [125I]I-[(4-hydroxyphenyl)ethyl]maleimide ([125I]I-HPEM) labeling strategy. GLGK was site-specifically coupled to human epidermal growth factor receptor 2 (HER2)-targeting ADAPT6. Conjugates without the cleavable linker were used as controls and all constructs were labeled with lutetium-177 (177Lu). [125I]I-HPEM was coupled to ADAPT6 at the C-terminus. Biodistribution of all constructs was evaluated in NMRI mice 4 h after injection. Specific binding to HER2-expressing cells in vitro was demonstrated for all constructs. No significant difference in kidney uptake was observed between the [177Lu]Lu-2,2 ',2",2"'-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid-GLGK-conjugates and the controls. The renal activity of [125I]I-HPEM-ADAPT6 was significantly lower compared with all other constructs. In conclusion, the incorporation of the cleavable GLGK-linker did not result in lower renal retention. Therefore, the present study emphasized that, in order to achieve a reduction of renal retention, alternative molecular design strategies may be required for different targeting agents.
|
|
| 9. |
- Mead, Timothy J., et al.
(författare)
-
Combined genetic-pharmacologic inactivation of tightly linked ADAMTS proteases in temporally specific windows uncovers distinct roles for versican proteolysis and glypican-6 in cardiac development
- 2024
-
Ingår i: Matrix Biology. - 0945-053X. ; 131, s. 1-16
-
Tidskriftsartikel (refereegranskat)abstract
- Extracellular matrix remodeling mechanisms are understudied in cardiac development and congenital heart defects. We show that matrix-degrading metalloproteases ADAMTS1 and ADAMTS5, are extensively co-expressed during mouse cardiac development. The mouse mutants of each gene have mild cardiac anomalies, however, their combined genetic inactivation to elicit cooperative roles is precluded by tight gene linkage. Therefore, we coupled Adamts1 inactivation with pharmacologic ADAMTS5 blockade to uncover stage-specific cooperative roles and investigated their potential substrates in mouse cardiac development. ADAMTS5 blockade was achieved in Adamts1 null mouse embryos using an activity-blocking monoclonal antibody during distinct developmental windows spanning myocardial compaction or cardiac septation and outflow tract rotation. Synchrotron imaging, RNA in situ hybridization, immunofluorescence microscopy and electron microscopy were used to determine the impact on cardiac development and compared to Gpc6 and ADAMTS-cleavage resistant versican mutants. Mass spectrometry-based N-terminomics was used to seek relevant substrates. Combined inactivation of ADAMTS1 and ADAMTS5 prior to 12.5 days of gestation led to dramatic accumulation of versican-rich cardiac jelly and inhibited formation of compact and trabecular myocardium, which was also observed in mice with ADAMTS cleavage-resistant versican. Combined inactivation after 12.5 days impaired outflow tract development and ventricular septal closure, generating a tetralogy of Fallot-like defect. N-terminomics of combined ADAMTS knockout and control hearts identified a cleaved glypican-6 peptide only in the controls. ADAMTS1 and ADAMTS5 expression in cells was associated with specific glypican-6 cleavages. Paradoxically, combined ADAMTS1 and ADAMTS5 inactivation reduced cardiac glypican-6 and outflow tract Gpc6 transcription. Notably, Gpc6−/− hearts demonstrated similar rotational defects as combined ADAMTS inactivated hearts and both had reduced hedgehog signaling. Thus, versican proteolysis in cardiac jelly at the canonical Glu441-Ala442 site is cooperatively mediated by ADAMTS1 and ADAMTS5 and required for proper ventricular cardiomyogenesis, whereas, reduced glypican-6 after combined ADAMTS inactivation impairs hedgehog signaling, leading to outflow tract malrotation.
|
|
| 10. |
- Nandadasa, Sumeda, et al.
(författare)
-
A new mouse mutant with cleavage-resistant versican and isoform-specific versican mutants demonstrate that proteolysis at the Glu441-Ala442 peptide bond in the V1 isoform is essential for interdigital web regression
- 2021
-
Ingår i: Matrix Biology Plus. - : Elsevier BV. - 2590-0285. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Two inherent challenges in the mechanistic interpretation of protease-deficient phenotypes are defining the specific substrate cleavages whose reduction generates the phenotypes and determining whether the phenotypes result from loss of substrate function, substrate accumulation, or loss of a function(s) embodied in the substrate fragments. Hence, recapitulation of a protease-deficient phenotype by a cleavage-resistant substrate would stringently validate the importance of a proteolytic event and clarify the underlying mechanisms. Versican is a large proteoglycan required for development of the circulatory system and proper limb development, and is cleaved by ADAMTS proteases at the Glu441-Ala442 peptide bond located in its alternatively spliced GAGβ domain. Specific ADAMTS protease mutants have impaired interdigit web regression leading to soft tissue syndactyly that is associated with reduced versican proteolysis. Versikine, the N-terminal proteolytic fragment generated by this cleavage, restores interdigit apoptosis in ADAMTS mutant webs. Here, we report a new mouse transgene, VcanAA, with validated mutations in the GAGβ domain that specifically abolish this proteolytic event. VcanAA/AA mice have partially penetrant hindlimb soft tissue syndactyly. However, Adamts20 inactivation in VcanAA/AA mice leads to fully penetrant, more severe syndactyly affecting all limbs, suggesting that ADAMTS20 cleavage of versican at other sites or of other substrates is an additional requirement for web regression. Indeed, immunostaining with a neoepitope antibody against a cleavage site in the versican GAGα domain demonstrated reduced staining in the absence of ADAMTS20. Significantly, mice with deletion of Vcan exon 8, encoding the GAGβ domain, consistently developed soft tissue syndactyly, whereas mice unable to include exon 7, encoding the GAGα domain in Vcan transcripts, consistently had fully separated digits. These findings suggest that versican is cleaved within each GAG-bearing domain during web regression, and affirms that proteolysis in the GAGβ domain, via generation of versikine, has an essential role in interdigital web regression.
|
|
