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| 3. |
- Björklund, Jesper, 1979, et al.
(författare)
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Scientific Merits and Analytical Challenges ofTree-Ring Densitometry
- 2019
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Ingår i: Reviews of Geophysics. - : American Geophysical Union (AGU). - 8755-1209 .- 1944-9208. ; 57:4, s. 1224-1264
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Tidskriftsartikel (refereegranskat)abstract
- X-ray microdensitometry on annually resolved tree-ring samples has gained an exceptional position in last-millennium paleoclimatology through the maximum latewood density (MXD) parameter, but also increasingly through other density parameters. For 50 years, X-ray based measurement techniques have been the de facto standard. However, studies report offsets in the mean levels for MXD measurements derived from different laboratories, indicating challenges of accuracy and precision. Moreover, reflected visible light-based techniques are becoming increasingly popular, and wood anatomical techniques are emerging as a potentially powerful pathway to extract density information at the highest resolution. Here we review the current understanding and merits of wood density for tree-ring research, associated microdensitometric techniques, and analytical measurement challenges. The review is further complemented with a careful comparison of new measurements derived at 17 laboratories, using several different techniques. The new experiment allowed us to corroborate and refresh "long-standing wisdom" but also provide new insights. Key outcomes include (i) a demonstration of the need for mass/volume-based recalibration to accurately estimate average ring density; (ii) a substantiation of systematic differences in MXD measurements that cautions for great care when combining density data sets for climate reconstructions; and (iii) insights into the relevance of analytical measurement resolution in signals derived from tree-ring density data. Finally, we provide recommendations expected to facilitate futureinter-comparability and interpretations for global change research.
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| 7. |
- Kogan, PS, et al.
(författare)
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Uncovering the molecular identity of cardiosphere-derived cells (CDCs) by single-cell RNA sequencing
- 2022
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Ingår i: Basic research in cardiology. - : Springer Science and Business Media LLC. - 1435-1803 .- 0300-8428. ; 117:1, s. 11-
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Tidskriftsartikel (refereegranskat)abstract
- Cardiosphere-derived cells (CDCs) generated from human cardiac biopsies have been shown to have disease-modifying bioactivity in clinical trials. Paradoxically, CDCs’ cellular origin in the heart remains elusive. We studied the molecular identity of CDCs using single-cell RNA sequencing (sc-RNAseq) in comparison to cardiac non-myocyte and non-hematopoietic cells (cardiac fibroblasts/CFs, smooth muscle cells/SMCs and endothelial cells/ECs). We identified CDCs as a distinct and mitochondria-rich cell type that shared biological similarities with non-myocyte cells but not with cardiac progenitor cells derived from human-induced pluripotent stem cells. CXCL6 emerged as a new specific marker for CDCs. By analysis of sc-RNAseq data from human right atrial biopsies in comparison with CDCs we uncovered transcriptomic similarities between CDCs and CFs. By direct comparison of infant and adult CDC sc-RNAseq data, infant CDCs revealed GO-terms associated with cardiac development. To analyze the beneficial effects of CDCs (pro-angiogenic, anti-fibrotic, anti-apoptotic), we performed functional in vitro assays with CDC-derived extracellular vesicles (EVs). CDC EVs augmented in vitro angiogenesis and did not stimulate scarring. They also reduced the expression of pro-apoptotic Bax in NRCMs. In conclusion, CDCs were disclosed as mitochondria-rich cells with unique properties but also with similarities to right atrial CFs. CDCs displayed highly proliferative, secretory and immunomodulatory properties, characteristics that can also be found in activated or inflammatory cell types. By special culture conditions, CDCs earn some bioactivities, including angiogenic potential, which might modify disease in certain disorders.
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| 8. |
- MacKay, Craig, et al.
(författare)
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Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2
- 2010
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 142:1, s. 65-76
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Tidskriftsartikel (refereegranskat)abstract
- DNA interstrand crosslinks (ICLs) are highly toxic because they block the progression of replisomes. The Fanconi Anemia (FA) proteins, encoded by genes that are mutated in FA, are important for repair of ICLs. The FA core complex catalyzes the monoubiquitination of FANCD2, and this event is essential for several steps of ICL repair. However, how monoubiquitination of FANCD2 promotes ICL repair at the molecular level is unknown. Here, we describe a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2. FAN1 exhibits endonuclease activity toward 50 flaps and has 5' exonuclease activity, and these activities are mediated by an ancient VRR_nuc domain. Depletion of FAN1 from human cells causes hypersensitivity to ICLs, defects in ICL repair, and genome instability. These data at least partly explain how ubiquitination of FANCD2 promotes DNA repair.
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| 9. |
- Sielemann, K, et al.
(författare)
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Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes
- 2020
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Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular diseases are the number one cause of morbidity and mortality worldwide, but the underlying molecular mechanisms remain not well understood. Cardiomyopathies are primary diseases of the heart muscle and contribute to high rates of heart failure and sudden cardiac deaths. Here, we distinguished four different genetic cardiomyopathies based on gene expression signatures. In this study, RNA-Sequencing was used to identify gene expression signatures in myocardial tissue of cardiomyopathy patients in comparison to non-failing human hearts. Therefore, expression differences between patients with specific affected genes, namely LMNA (lamin A/C), RBM20 (RNA binding motif protein 20), TTN (titin) and PKP2 (plakophilin 2) were investigated. We identified genotype-specific differences in regulated pathways, Gene Ontology (GO) terms as well as gene groups like secreted or regulatory proteins and potential candidate drug targets revealing specific molecular pathomechanisms for the four subtypes of genetic cardiomyopathies. Some regulated pathways are common between patients with mutations in RBM20 and TTN as the splice factor RBM20 targets amongst other genes TTN, leading to a similar response on pathway level, even though many differentially expressed genes (DEGs) still differ between both sample types. The myocardium of patients with mutations in LMNA is widely associated with upregulated genes/pathways involved in immune response, whereas mutations in PKP2 lead to a downregulation of genes of the extracellular matrix. Our results contribute to further understanding of the underlying molecular pathomechanisms aiming for novel and better treatment of genetic cardiomyopathies.
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| 11. |
- Al-Dajani, Haya, et al.
(författare)
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A multi-voiced account of family entrepreneuring research : expanding the agenda of family entrepreneurship
- 2023
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Ingår i: International Journal of Entrepreneurial Behaviour & Research. - : Emerald Group Publishing Limited. - 1355-2554 .- 1758-6534.
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThis conceptual, multi-voiced paper aims to collectively explore and theorize family entrepreneuring, which is a research stream dedicated to investigating the emergence and becoming of entrepreneurial phenomena in business families and family firms.Design/methodology/approachBecause of the novelty of this research stream, the authors asked 20 scholars in entrepreneurship and family business to reflect on topics, methods and issues that should be addressed to move this field forward.FindingsAuthors highlight key challenges and point to new research directions for understanding family entrepreneuring in relation to issues such as agency, processualism and context.Originality/valueThis study offers a compilation of multiple perspectives and leverage recent developments in the fields of entrepreneurship and family business to advance research on family entrepreneuring.
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| 13. |
- Fleischmann, K, et al.
(författare)
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A Schilder type theorem for super-Brownian motion
- 1996
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Ingår i: CANADIAN JOURNAL OF MATHEMATICS-JOURNAL CANADIEN DE MATHEMATIQUES. ; 48:3, s. 542-568
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Tidskriftsartikel (refereegranskat)abstract
- Let X be a d-dimensional continuous super-Brownian motion with branching rate epsilon, which might be described symbolically by the ''stochastic equation'' dX(t) = Delta*X(t)dt + root 2 epsilon X(t)dW(t) with dW(t)/dt a space-time white noise. A Schilder
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| 14. |
- Frid, Casey J., et al.
(författare)
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Low-wealth entrepreneurs and access to external financing
- 2016
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Ingår i: International Journal of Entrepreneurial Behaviour & Research. - : Emerald Group Publishing Limited. - 1355-2554 .- 1758-6534. ; 22:4, s. 531-555
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Tidskriftsartikel (refereegranskat)abstract
- Purpose– The purpose of this paper is to explore the relationship between low-wealth business founders in the USA and external startup funding. Specifically, the authors test whether a founders’ low personal net worth is correlated with a lower probability of acquiring funding from outside sources during the business creation process.Design/methodology/approach– The authors use a double-hurdle Cragg model to jointly estimate: first, the decision to acquire external financing; and second, the amount received. The sample is the US-based Panel Study of Entrepreneurial Dynamics II (PSED II). The PSED II tracks business founders attempting to start ventures from 2005 to 2012.Findings– Receipt of outside financing during business formation is largely determined by the business founder’s personal finances (controlling for human capital, venture type and industry, and whether money was sought in the first place). A higher household net worth results in larger amounts of external funding received. Low-wealth business founders, therefore, are less likely to get external funds, and they receive lower amounts when they do. The disparity between low-and high-wealth business founders is more pronounced for formal, monitored sources of external financing such as bank loans.Research limitations/implications– Because the study eliminates survivor bias by using a nationally representative sample of business founders who are in the venture creation process, the findings apply to both successful business founders and those who disengaged during the business creation process. The authors offer insights into the sources and amounts of external funds acquired by individuals across all levels of wealth. The authors accomplish this by disaggregating business founders into wealth quintiles. The study demonstrates the importance of personal wealth as a factor in acquiring external startup financing compared to human capital, industry, or personal characteristics.Social implications– If the ability to acquire external funding is significantly constrained, the quality of the opportunity and the skill of the business founder may be less a determinant of success at creating a new business as prior studies have suggested. Consequently, entrepreneurship (as measured by business formation) as a path toward upward, socioeconomic mobility will be afforded only to those individuals with sufficient financial endowments at the outset.Originality/value– Unlike prior studies, the data used are not subject to survivor bias or an underrepresentation of self-employment. The statistical model jointly estimates acquisition of financing and the amount received. This resolves selection and censoring problems. Finally, the dependent variables directly measure liquidity constraints in the context of business formation, that is, before a new venture is created. Prior research contexts have typically studied existing businesses, and are therefore not true examinations of conditions affecting business creation.
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| 15. |
- Frid, Casey J., et al.
(författare)
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The influence of financial 'skin in the game' on new venture creation
- 2015
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Ingår i: Academy of Entrepreneurship Journal. - 1087-9595 .- 1528-2686. ; 21:2, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- A common theme in entrepreneurship research is that the founder must be committed in order for a new venture to succeed. Although investments of time and sweat equity can indicate commitment, external stakeholders may prefer founders who have made a significant, personal financial stake in their nascent ventures. This personal financial commitment is known as "skin in the game." Founders that invest more of their own money into their ventures signal greater commitment to potential business partners, suppliers, and resource providers.This study examines the amount of personal funds invested by 1,214 nascent entrepreneurs in the United States, between the years of 2005 and 2012. Findings demonstrate that the dollar amount of personal money invested prior to launch does not significantly impact the creation of new firms. However, nascent entrepreneurs that invest larger amounts as a proportion of their net income are more likely to succeed and are less likely to disengage from the process. Personal funds invested as a proportion of net income may therefore be a better measure of future success than the precise amount. This study also shows that the founder's human capital, perceptions of community support, and industry characteristics influence startup outcomes.
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| 16. |
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| 17. |
- Hermelijn, S, et al.
(författare)
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Development of a core outcome set for congenital pulmonary airway malformations: study protocol of an international Delphi survey
- 2021
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:4, s. e044544-
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Tidskriftsartikel (refereegranskat)abstract
- A worldwide lack of consensus exists on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM) even though the incidence is increasing. Either a surgical resection is performed or a wait-and-see policy is employed, depending on the treating physician. Management is largely based on expert opinion and scientific evidence is scarce. Wide variations in outcome measures are seen between studies making comparison difficult thus highlighting the lack of universal consensus in outcome measures as well. We aim to define a core outcome set which will include the most important core outcome parameters for paediatric patients with an asymptomatic CPAM.Methods and analysisThis study will include a critical appraisal of the current literature followed by a three-stage Delphi process with two stakeholder groups. One surgical group including paediatric as well as thoracic surgeons, and a non-surgeon group including paediatric pulmonologists, intensive care and neonatal specialists. All participants will score outcome parameters according to their level of importance and the most important parameters will be determined by consensus.Ethics and disseminationElectronic informed consent will be obtained from all participants. Ethical approval is not required. After the core outcome set has been defined, we intend to design an international randomised controlled trial: the COllaborative Neonatal NEtwork for the first CPAM Trial, which will be aimed at determining the optimal management of patients with asymptomatic CPAM.
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| 18. |
- Kersten, CM, et al.
(författare)
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The Management of Asymptomatic Congenital Pulmonary Airway Malformation: Results of a European Delphi Survey
- 2022
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Ingår i: Children (Basel, Switzerland). - : MDPI AG. - 2227-9067. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Consensus on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM) is lacking, and comparison between studies remains difficult due to a large variety in outcome measures. We aimed to define a core outcome set (COS) for pediatric patients with an asymptomatic CPAM. An online, three-round Delphi survey was conducted in two stakeholder groups of specialized caregivers (surgeons and non-surgeons) in various European centers. Proposed outcome parameters were scored according to level of importance, and the final COS was established through consensus. A total of 55 participants (33 surgeons, 22 non-surgeons) from 28 centers in 13 European countries completed the three rounds and rated 43 outcome parameters. The final COS comprises seven outcome parameters: respiratory insufficiency, surgical complications, mass effect/mediastinal shift (at three time-points) and multifocal disease (at two time-points). The seven outcome parameters included in the final COS reflect the diversity in priorities among this large group of European participants. However, we recommend the incorporation of these outcome parameters in the design of future studies, as they describe measurable and validated outcomes as well as the accepted age at measurement.
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| 23. |
- Wagner-Drouet, E, et al.
(författare)
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Comparison of Cytomegalovirus-Specific Immune Cell Response to Proteins versus Peptides Using an IFN-γ ELISpot Assay after Hematopoietic Stem Cell Transplantation
- 2021
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Ingår i: Diagnostics (Basel, Switzerland). - : MDPI AG. - 2075-4418. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Measuring CMV-specific cellular immunity may improve the risk stratification and management of patients. IFN-γ ELISpot assays, based on the stimulation of peripheral blood mononuclear cells with CMV pp65 and IE-1 proteins or peptides, have been validated in clinical settings. However, it remains unclear to which extend the T-cell response to synthetic peptides reflect that mediated by full-length proteins processed by antigen-presenting cells. We compared the stimulating ability of pp65 and IE-1 proteins and corresponding overlapping peptides in 16 HSCT recipients using a standardized IFN-γ ELISpot assay. Paired qualitative test results showed an overall 74.4% concordance. Discordant results were mainly due to low-response tests, with one exception. One patient with early CMV reactivation and graft-versus-host disease, sustained CMV DNAemia and high CD8+ counts showed successive negative protein-based ELISpot results but a high and sustained response to IE-1 peptides. Our results suggest that the response to exogenous proteins, which involves their uptake and processing by antigen-presenting cells, more closely reflects the physiological response to CMV infection, while the response to exogenous peptides may lead to artificial in vitro T-cell responses, especially in strongly immunosuppressed patients.
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| 24. |
- Wagner-Drouet, E, et al.
(författare)
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Standardized monitoring of cytomegalovirus-specific immunity can improve risk stratification of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation
- 2021
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 106:2, s. 363-374
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Tidskriftsartikel (refereegranskat)abstract
- Recurrence of cytomegalovirus reactivation remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Monitoring cytomegalovirus-specific cellular immunity using a standardized assay might improve the risk stratification of patients. A prospective multicenter study was conducted in 175 intermediate- and high-risk allogeneic hematopoietic stem cell transplant recipients under preemptive antiviral therapy. Cytomegalovirus-specific cellular immunity was measured using a standardized IFN-γ ELISpot assay (T-Track® CMV). Primary aim was to evaluate the suitability of measuring cytomegalovirus-specific immunity after end of treatment for a first cytomegalovirus reactivation to predict recurrent reactivation. 40/101 (39.6%) patients with a first cytomegalovirus reactivation experienced recurrent reactivations, mainly in the high-risk group (cytomegalovirus-seronegative donor/cytomegalovirus-seropositive recipient). The positive predictive value of T-Track® CMV (patients with a negative test after the first reactivation experienced at least one recurrent reactivation) was 84.2% in high-risk patients. Kaplan-Meier analysis revealed a higher probability of recurrent cytomegalovirus reactivation in high-risk patients with a negative test after the first reactivation (hazard ratio 2.73; p=0.007). Interestingly, a post-hoc analysis considering T-Track® CMV measurements at day 100 post-transplantation, a time point highly relevant for outpatient care, showed a positive predictive value of 90.0% in high-risk patients. Our results indicate that standardized cytomegalovirus-specific cellular immunity monitoring may allow improved risk stratification and management of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. This study was registered at www.clinicaltrials.gov as #NCT02156479.
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| 27. |
- Warhuus, Jan P., et al.
(författare)
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Ready or not? : Nascent entrepreneurs' actions and the acquisition of external financing
- 2021
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Ingår i: International Journal of Entrepreneurial Behaviour & Research. - : Emerald Group Publishing Limited. - 1355-2554 .- 1758-6534. ; 27:6, s. 1605-1628
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThis study offers empirical evidence from a nationally representative panel dataset of nascent entrepreneurs (PSED-II) regarding when external financing is acquired and how certain factors affect this timing during the cumulative process of nascent entrepreneurs taking actions toward establishing an operational entity. By assessing the relationship between the external financing event and the cumulative set of actions that nascent entrepreneurs undertake to create new businesses, we improve our understanding of how the timing of acquiring external financing affects organizational survival and growth.Design/methodology/approachWe apply nonparametric and semiparametric survival analysis techniques to a nationally representative panel dataset of nascent entrepreneurs. This ascertains the probability of an external financing event at any given moment in time and a set of startup conditions that we hypothesize will affect this timing. First, we use Kaplan-Meier analysis to explore when external financing occurs during new business creation. We then use discrete-time survival analysis to investigate whether certain startup conditions affect when external financing occurs. Finally, we conduct a test of independence to examine the external financing event relative to other startup activities completed during new business creation.FindingsNascent entrepreneurs tend to acquire external funding relatively late in the new venture startup process - on average, about two-thirds of the way from conceiving of the idea and becoming operational. They tend to take actions that are less resource-demanding early in the startup process to build their organizations to a fundable stage. Net worth tends to speed up the acquisition of external funding as wealthy entrepreneurs tend to ask for funding earlier in the process. Finally, entrepreneurs in capital-intensive industries do not seem to get outside funding before entrepreneurs in other industries.Originality/valueThis study is unique in three ways. First, we investigate the timing of the highly important external financing event. Timing is critical in unpacking and making sense of the very early stages of a new business and in guiding entrepreneurs and students about when to do what. Second, we do so in a subsample of preoperational, nascent, funded entrepreneurs derived from a nationally representative panel dataset of startup attempts. Third, our findings provide a counter-intuitive yet systematic understanding of organizational emergence and very early-stage financing.
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| 28. |
- Williams, Michael J., et al.
(författare)
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The Statin Target Hmgcr Regulates Energy Metabolism and Food Intake through Central Mechanisms
- 2022
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- The statin drug target, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is strongly linked to body mass index (BMI), yet how HMGCR influences BMI is not understood. In mammals, studies of peripheral HMGCR have not clearly identified a role in BMI maintenance and, despite considerable central nervous system expression, a function for central HMGCR has not been determined. Similar to mammals, Hmgcr is highly expressed in the Drosophila melanogaster brain. Therefore, genetic and pharmacological studies were performed to identify how central Hmgcr regulates Drosophila energy metabolism and feeding behavior. We found that inhibiting Hmgcr, in insulin-producing cells of the Drosophila pars intercerebralis (PI), the fly hypothalamic equivalent, significantly reduces the expression of insulin-like peptides, severely decreasing insulin signaling. In fact, reducing Hmgcr expression throughout development causes decreased body size, increased lipid storage, hyperglycemia, and hyperphagia. Furthermore, the Hmgcr induced hyperphagia phenotype requires a conserved insulin-regulated alpha-glucosidase, target of brain insulin (tobi). In rats and mice, acute inhibition of hypothalamic Hmgcr activity stimulates food intake. This study presents evidence of how central Hmgcr regulation of metabolism and food intake could influence BMI.
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