| 1. |
- Steneberg, Pär, et al.
(författare)
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PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients
- 2018
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Ingår i: JCI INSIGHT. - : American Society for Clinical Investigation. - 2379-3708. ; 3:12
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Tidskriftsartikel (refereegranskat)abstract
- AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced beta cell stress, and promoted beta cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro-and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.
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| 2. |
- Ali, Yusuf, et al.
(författare)
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The anterior chamber of the eye is a transplantation site that supports and enables visualisation of beta cell development in mice
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:5, s. 1007-1011
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Tidskriftsartikel (refereegranskat)abstract
- In vivo imaging of the developing pancreas is challenging due to the inaccessibility of the tissue. To circumvent this, on embryonic day 10.5 (E10.5) we transplanted a mouse developing pancreatic bud into the anterior chamber of the eye (ACE) to determine whether the eye is a useful transplant site to support pancreas development. We transplanted an E10.5 dorsal pancreatic bud into the ACE of a syngeneic recipient mouse. Using a mouse insulin promoter-green fluorescent protein (MIP-GFP) mouse as the tissue donor, we non-invasively imaged the pancreatic bud as it develops at single beta cell resolution across time. The transplanted pancreatic bud rapidly engrafts and vascularises when transplanted into the ACE. The pancreatic progenitor cells differentiate into exocrine and endocrine cells, including cells expressing insulin, glucagon and somatostatin. The morphology of the transplanted pancreatic bud resembles that of the native developing pancreas. Beta cells within the transplanted pancreatic bud respond to glucose in a manner similar to that of native fetal beta cells and superior to that of in vitro developed beta cells. Unlike in vitro grown pancreatic explants, pancreatic tissue developing in the ACE is vascularised, providing the developing pancreatic tissue with a milieu resembling the native situation. Altogether, we show that the ACE is able to support growth, differentiation and function of a developing pancreatic bud across time in vivo.
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| 3. |
- Annicotte, Jean-Sébastien, et al.
(författare)
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Pancreatic-duodenal homeobox 1 regulates expression of liver receptor homolog 1 during pancreas development.
- 2003
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 23:19, s. 6713-6124
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Tidskriftsartikel (refereegranskat)abstract
- Liver receptor homolog 1 (LRH-1) and pancreatic-duodenal homeobox 1 (PDX-1) are coexpressed in the pancreas during mouse embryonic development. Analysis of the regulatory region of the human LRH-1 gene demonstrated the presence of three functional binding sites for PDX-1. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed that PDX-1 bound to the LRH-1 promoter, both in cultured cells in vitro and during pancreatic development in vivo. Retroviral expression of PDX-1 in pancreatic cells induced the transcription of LRH-1, whereas reduced PDX-1 levels by RNA interference attenuated its expression. Consistent with direct regulation of LRH-1 expression by PDX-1, PDX-1(-/-) mice expressed smaller amounts of LRH-1 mRNA in the embryonic pancreas. Taken together, our data indicate that PDX-1 controls LRH-1 expression and identify LRH-1 as a novel downstream target in the PDX-1 regulatory cascade governing pancreatic development, differentiation, and function.
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| 4. |
- Berg, Staffan, et al.
(författare)
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Considerations in the developability of peptides for oral administration when formulated together with transient permeation enhancers
- 2022
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Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 628
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Tidskriftsartikel (refereegranskat)abstract
- This paper reviews many of the properties of a peptide that need to be considered prior to development as an oral dosage form when co-formulated with a permeation enhancer to improve oral bioavailability, including the importance and implications of peptide half-life on variability in pharmacokinetic profiles. Clinical consider-ations in terms of food and drug-drug interactions are also discussed. The paper further gives a brief overview how permeation enhancers overcome barriers that limit oral absorption of peptides and thereby improve their oral bioavailability, albeit bioavailabilities are still low single digit and variability is high.
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| 5. |
- Beskow, J., et al.
(författare)
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Innovative interfaces in MonAMI : The reminder
- 2008
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Ingår i: ICMI'08. - New York, NY, USA : ACM. - 9781605581989 ; , s. 199-200
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Konferensbidrag (refereegranskat)abstract
- This demo paper presents an early version of the Reminder, a prototype ECA developed in the European project MonAMI, which aims at "mainstreaming accessibility in consumer goods and services, using advanced technologies to ensure equal access, independent living and participation for all". The Reminder helps users to plan activities and to remember what to do. The prototypemerges mobile ECA technology with other, existing technologies:Google Calendar and a digital pen and paper. The solution allows users to continue using a paper calendar in the manner they are used to, whilst the ECA provides notifications on what has been written in the calendar. Users may ask questions such as "When was I supposed to meet Sara?" or "What's my schedule today"?
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| 6. |
- Beskow, Jonas, et al.
(författare)
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The MonAMI Reminder : a spoken dialogue system for face-to-face interaction
- 2009
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Ingår i: Proceedings of the 10th Annual Conference of the International Speech Communication Association, INTERSPEECH 2009. - Brighton, U.K. ; , s. 300-303
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Konferensbidrag (refereegranskat)abstract
- We describe the MonAMI Reminder, a multimodal spoken dialogue system which can assist elderly and disabled people in organising and initiating their daily activities. Based on deep interviews with potential users, we have designed a calendar and reminder application which uses an innovative mix of an embodied conversational agent, digital pen and paper, and the web to meet the needs of those users as well as the current constraints of speech technology. We also explore the use of head pose tracking for interaction and attention control in human-computer face-to-face interaction.
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| 7. |
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| 8. |
- Boucher, Marie-Josée, et al.
(författare)
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The homeodomain-interacting protein kinase 2 regulates insulin promoter factor-1/pancreatic duodenal homeobox-1 transcriptional activity
- 2009
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 150:1, s. 87-97
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Tidskriftsartikel (refereegranskat)abstract
- The homeodomain transcription factor insulin promoter factor (IPF)-1/pancreatic duodenal homeobox (PDX)-1 plays a crucial role in both pancreas development and maintenance of beta-cell function. Targeted disruption of the Ipf1/Pdx1 gene in beta-cells of mice leads to overt diabetes and reduced Ipf1/Pdx1 gene expression results in decreased insulin expression and secretion. In humans, mutations in the IPF1 gene have been linked to diabetes. Hence, the identification of molecular mechanisms regulating the transcriptional activity of this key transcription factor is of great interest. Herein we analyzed homeodomain-interacting protein kinase (Hipk) 2 expression in the embryonic and adult pancreas by in situ hybridization and RT-PCR. Moreover, we functionally characterized the role of HIPK2 in regulating IPF1/PDX1 transcriptional activity by performing transient transfection experiments and RNA interference. We show that Hipk2 is expressed in the developing pancreatic epithelium from embryonic d 12-15 but that the expression becomes preferentially confined to pancreatic endocrine cells at later developmental stages. Moreover, we show that HIPK2 positively influences IPF1/PDX1 transcriptional activity and that the kinase activity of HIPK2 is required for this effect. We also demonstrate that HIPK2 directly phosphorylates the C-terminal portion of IPF1/PDX1. Taken together, our data provide evidence for a new mechanism by which IPF1/PDX1 transcriptional activity, and thus possibly pancreas development and/or beta-cell function, is regulated.
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| 9. |
- Correa-Medina, Mayrin, et al.
(författare)
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MicroRNA miR-7 is preferentially expressed in endocrine cells of the developing and adult human pancreas.
- 2009
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Ingår i: Gene Expression Patterns. - : Elsevier BV. - 1567-133X .- 1872-7298. ; 9:4, s. 193-9
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNA) are small non-coding RNAs that inhibit gene expression through binding to complementary messenger RNA sequences. miRNAs have been predicted to target genes important for pancreas development, proper endocrine cell function and metabolism. We previously described that miRNA-7 (miR-7) was the most abundant and differentially expressed islet miRNA, with 200-fold higher expression in mature human islets than in acinar tissue. Here we have analyzed the temporal and spatial expression of miR-7 in human fetal pancreas from 8 to 22 weeks of gestational age (wga). Human fetal (8-22wga) and adult pancreases were processed for immunohistochemistry, in situ hybridization, and quantitative RT-PCR of miRNA and mRNA. miR-7 was expressed in the human developing pancreas from around 9wga and reached its maximum expression levels between 14 and 18wga, coinciding with the exponential increase of the pancreatic endocrine hormones. Throughout development miR-7 expression was preferentially localized to endocrine cells and its expression persisted in the adult pancreas. The present study provides a detailed analysis of the spatiotemporal expression of miR-7 in developing human pancreas. The specific localization of miR-7 expression to fetal and adult endocrine cells indicates a potential role for miR-7 in endocrine cell differentiation and/or function. Future functional studies of a potential role for miR-7 function in islet cell differentiation and physiology are likely to identify novel targets for the treatment of diabetes and will lead to the development of improved protocols for generating insulin-producing cells for cell replacement therapy.
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| 10. |
- Coutinho, Alexandra, et al.
(författare)
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Later Stone Age human hair from Vaalkrans Shelter, Cape Floristic Region of South Africa, reveals genetic affinity to Khoe groups
- 2021
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Ingår i: American Journal of Physical Anthropology. - : John Wiley & Sons. - 0002-9483 .- 1096-8644. ; 174:4, s. 701-713
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies show that the indigenous people of the southern Cape of South Africa were dramatically impacted by the arrival of European colonists starting ~400 years ago and their descendants are today mixed with Europeans and Asians. To gain insight on the occupants of the Vaalkrans Shelter located at the southernmost tip of Africa, we investigated the genetic make-up of an individual who lived there about 200 years ago. We further contextualize the genetic ancestry of this individual among prehistoric and current groups. From a hair sample excavated at the shelter, which was indirectly dated to about 200 years old, we sequenced the genome (1.01 times coverage) of a Later Stone Age individual. We analyzed the Vaalkrans genome together with genetic data from 10 ancient (pre-colonial) individuals from southern Africa spanning the last 2000 years. We show that the individual from Vaalkrans was a man who traced ~80% of his ancestry to local southern San hunter–gatherers and ~20% to a mixed East African-Eurasian source. This genetic make-up is similar to modern-day Khoekhoe individuals from the Northern Cape Province (South Africa) and Namibia, but in the southern Cape, the Vaalkrans man's descendants have likely been assimilated into mixed-ancestry “Coloured” groups. The Vaalkrans man's genome reveals that Khoekhoe pastoralist groups/individuals lived in the southern Cape as late as 200 years ago, without mixing with non-African colonists or Bantu-speaking farmers. Our findings are also consistent with the model of a Holocene pastoralist migration, originating in Eastern Africa, shaping the genomic landscape of historic and current southern African populations.
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