Gene expression studies of pregastrulation development: the basement membrane is essential for cell differentiation

Basement membranes (BMs) are sheet-like structures of extracellular matrix. They act as a supporting structure but can also significantly influence cellular behavior in development, tissue homeostasis and disease. Laminins, a major BM component, are multidomain proteins, consisting of three polypeptide chains (α, β and γ). During pregastrulation development, stem cells convert and epithelial tissues are formed. This process is faithfully mimicked in vitro by embryoid body (EB) cultures. Fibroblast growth factor (FGF) signaling is crucial when the step-like process of EB development is initiated with the formation of an endoderm. A subendodermal BM is formed, in which the globular domains LG4-5 of the laminin α1 chain (α1LG4-5) are responsible for the induction of the epiblast EBs derived form embryonic stem (ES) cells, modified to repress FGF receptor signaling, have been described before. However, a full-scale analysis of the transcriptome was missing. We therefore analysed these EBs at four time points during differentiation by the use of microarray technique. An extensive catalogue of affected genes was reported. A majority of the genes directed by FGF signalling were encoding BM and endodermal proteins. In addition, we also analysed the expression profile of wild type EBs. In both these studies, we found interesting genes not previously described in early development or identified as FGF targets. Hopefully, our gene catalogue will be a valuable source for the scientific community interested in FGF signaling, developmental biology and stem cell research. Furthermore, a gene expression study was set up to get a better insight of epiblast inducement by α1LG4-5. EBs derived form ES cells with a targeted deletion of the α1LG4-5 domains were analysed. To our surprise, we found several indications of an incomplete differentiation of the visceral endoderm. We therefore hypothesize a novel autocrine mechanism for α1LG4-5 in regulating the developing endoderm. We also suggest novel roles for laminin LG4-5 in the neuromuscular system. Using laminin α2 chain deficient mice overexpressing laminin α1 chain lacking the LG4-5 domains, we show that these domains, and consequently binding to the receptor dystroglycan are not crucial in diaphragm and heart, but essential in the peripheral nervous system

Carotenoid Intake and Serum Concentration in Young Finnish Children and Their Relation with Fruit and Vegetable Consumption

Fruit and vegetable intake has been associated with a reduced risk of many chronic diseases. These foods are the main dietary source of carotenoids. The aim of the present study was to evaluate the associations between dietary intake and serum concentrations of alpha- and beta-carotene in a sample of young Finnish children from the population-based birth cohort of the Type 1 Diabetes Prediction and Prevention (DIPP) Study. The current analysis comprised 3-day food records and serum samples from 207 children aged 1, 2 and 3 years. Spearman and partial correlations, as well as a cross-classification analyses, were used to assess the relationship between dietary intake and the corresponding biomarkers. Serum concentrations of alpha- and beta-carotene were significantly higher among the 1-year-old compared to the 3-year-old children. Dietary intakes of alpha- and beta-carotene correlated significantly with their respective serum concentrations in all age groups, the association being highest at the age of 1 year (alpha-carotene r = 0.48; p <0.001 and beta-carotene r = 0.47; p <0.001), and lowest at the age of 3 years (alpha-carotene r = 0.44; p <0.001 and beta-carotene r = 0.30; p <0.001). A cross-classification showed that 72-81% of the participants were correctly classified to the same or adjacent quartile, when comparing the reported dietary intakes and the concentrations of the corresponding carotenoid in serum. The 3-day food record seems to be reasonably valid in the assessment of root vegetable consumption among young Finnish children. Root vegetables were the main dietary source of both carotenoids in all age groups. The high consumption of commercial baby foods among the 1-year-old children was reflected in the relatively high dietary intake and serum concentration of both carotenoids.Peer reviewe

Consumption of differently processed milk products in infancy and early childhood and the risk of islet autoimmunity

Several prospective studies have shown an association between cows’ milk consumption and the risk of islet autoimmunity and/or type 1 diabetes. We wanted to study whether processing of milk plays a role. A population-based birth cohort of 6081 children with HLA-DQB1-conferred risk to type 1 diabetes was followed until the age of 15 years. We included 5545 children in the analyses. Food records were completed at the ages of 3 and 6 months and 1, 2, 3, 4 and 6 years, and diabetes-associated autoantibodies were measured at 3–12-month intervals. For milk products in the food composition database, we used conventional and processing-based classifications. We analysed the data using a joint model for longitudinal and time-to-event data. By the age of 6 years, islet autoimmunity developed in 246 children. Consumption of all cows’ milk products together (energy-adjusted hazard ratio 1·06; 95 % CI 1·02, 1·11; P = 0·003), non-fermented milk products (1·06; 95 % CI 1·01, 1·10; P = 0·011) and fermented milk products (1·35; 95 % CI 1·10, 1·67; P = 0·005) was associated with an increased risk of islet autoimmunity. The early milk consumption was not associated with the risk beyond 6 years. We observed no clear differences based on milk homogenisation and heat treatment. Our results are consistent with the previous studies, which indicate that high milk consumption may cause islet autoimmunity in children at increased genetic risk. The study did not identify any specific type of milk processing that would clearly stand out as a sole risk factor apart from other milk products.Peer reviewe

A Joint Modeling Approach for Childhood Meat, Fish and Egg Consumption and the Risk of Advanced Islet Autoimmunity

Several dietary factors have been suspected to play a role in the development of advanced islet autoimmunity (IA) and/or type 1 diabetes (T1D), but the evidence is fragmentary. A prospective population-based cohort of 6081 Finnish newborn infants with HLA-DQB1-conferred susceptibility to T1D was followed up to 15 years of age. Diabetes-associated autoantibodies and diet were assessed at 3-to 12-month intervals. We aimed to study the association between consumption of selected foods and the development of advanced IA longitudinally with Cox regression models (CRM), basic joint models (JM) and joint latent class mixed models (JLCMM). The associations of these foods to T1D risk were also studied to investigate consistency between alternative endpoints. The JM showed a marginal association between meat consumption and advanced IA: the hazard ratio adjusted for selected confounding factors was 1.06 (95% CI: 1.00, 1.12). The JLCMM identified two classes in the consumption trajectories of fish and a marginal protective association for high consumers compared to low consumers: the adjusted hazard ratio was 0.68 (0.44, 1.05). Similar findings were obtained for T1D risk with adjusted hazard ratios of 1.13 (1.02, 1.24) for meat and 0.45 (0.23, 0.86) for fish consumption. Estimates from the CRMs were closer to unity and CIs were narrower compared to the JMs. Findings indicate that intake of meat might be directly and fish inversely associated with the development of advanced IA and T1D, and that disease hazards in longitudinal nutritional epidemiology are more appropriately modeled by joint models than with naive approaches

A novel processing-based classification and conventional food grouping to estimate milk product consumption in Finnish children

As more information is needed about the health aspects of milk processing; we classified milk products based on their homogenisation and heat-treatment history in the following inclusive classes: (i) homogenised, (ii) non-homogenised, (iii) fat-free; and (i) low-pasteurised or less heat-treated, (ii) high-pasteurised at cows’ milk products (median consumption 511 g d−1); at 3 y most of the consumed milk products were low-pasteurised or less heat-treated and homogenised. In contrast to children aged 3 y, almost all milk products consumed by infants aged 6 months were pasteurised at high temperature or sterilised.</p

Consumption of differently processed milk products and the risk of asthma in children

Background Consumption of unprocessed cow's milk has been associated with a lower risk of childhood asthma and/or atopy. Not much is known about differently processed milk products. We aimed to study the association between the consumption of differently processed milk products and asthma risk in a Finnish birth cohort. Methods We included 3053 children from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study. Asthma and its subtypes were assessed at the age of 5 years, and food consumption by food records, at the age of 3 and 6 months and 1, 2, 3, 4, and 5 years. We used conventional and processing (heat treatment and homogenization)-based classifications for milk products. The data were analyzed using a joint model for longitudinal and time-to-event data. Results At the age of 5 years, 184 (6.0%) children had asthma, of whom 101 (54.9%) were atopic, 75 (40.8%) were nonatopic, and eight (4.3%) could not be categorized. Consumption of infant formulas [adjusted hazard ratio (95% confidence intervals) 1.15 (1.07, 1.23), p < .001] and strongly heat-treated milk products [1.06 (1.01, 1.10), p = .01] was associated with the risk of all asthma. Consumption of all cow's milk products [1.09 (1.03, 1.15), p = .003], nonfermented milk products [1.08 (1.02, 1.14), p = .008], infant formulas [1.23 (1.13, 1.34), p < .001], and strongly heat-treated milk products [1.08 (1.02, 1.15), p = .006] was associated with nonatopic asthma risk. All these associations remained statistically significant after multiple testing correction. Conclusions High consumption of infant formula and other strongly heat-treated milk products may be associated with the development of asthma

Distinct molecular signatures of clinical clusters in people with type 2 diabetes:an IMI-RHAPSODY study

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous diseas

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes

OBJECTIVELatent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.RESEARCH DESIGN AND METHODSWe performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396).RESULTSThe leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.CONCLUSIONSOur results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.Peer reviewe

Cross Education; : The effect of 10 weeks of unilateral resistance training on strength and hypertrophy

Abstract    Aim    The main purpose of this study was to investigate Cross Education (CE), and how gender, detraining and leg dominance affects CE in previously untrained subjects when conducting a unilateral resistance training program. We also investigated if unilateral resistance training can give a hypertrophic response.    Method   Twenty healthy previously untrained individuals, 10 females and 10 males, were recruited as volunteer participants. The participants were randomly assigned to train either left or right leg. The training intervention was 10 weeks (34 sessions) of unilateral resistance training in the leg press and leg extension, sixteen of the participants fulfilled the criteria for inclusion. After two initial familiarization the participants trained conventional resistance training three times a week (week 1-3, 5-7 and 9-10) and Blood Flow Restriction Training (BFRT) five times a week (week 4 and 8). One repetition maximum for both legs in the leg press and leg extension was tested pre-, post and post20 to the training intervention as well as ultrasound measurements of muscle thickness.   Results    The ten-week training period resulted in a significant increase of maximal strength for the untrained leg 18,9 %, (16,6) (p &lt; 0,01) in the leg press and 6,7 %, (3,7) (p &lt; 0,05) in the leg extension. When comparisons between gender were made only men had a significant increase 26,5 %, (16,7) (p &lt; 0,01) in the leg press and 9,9 %, (4,7) (p &lt; 0,05) in the leg extension. Also, we saw a significant difference between women and men on a group level. Comparisons of dominant vs non-dominant leg showed that training the dominant leg resulted in a significant increase of maximal strength in the untrained leg in both the leg press 22 %, (17,9) (p &lt; 0,01) and leg extension 10,1 %, (4,3) (p &lt; 0,05). The maximal strength in the untrained leg was not significantly altered by the detraining period and a significant increase of muscle thickness could be seen in the untrained leg at MP50 4,7 %, (1,3) (p &lt; 0,01).   Conclusion    The conclusions are that a ten week unilateral resistance training intervention results in a CE effect for men but not for women and that this type of training also can result in an increased muscle thickness in the untrained leg. Our findings also supports that training the dominant limb has superior effect on achieving a CE effect. Lastly we conclude that a twenty week detraining period did not affect the CE achieved strength.   Abstrakt    Syfte     Studiens huvudsakliga syfte var att undersöka Cross Education (CE) och hur kön, viloperiod och ben-dominans påverkar CE hos otränade individer när man undergår ett unilateralt styrketräningsprogram. Vi undersökte även om ett unilateral styrketräning kunde ge ett hypertrofisvar.    Metod    Tjugo friska otränade och för närvarande inaktiva individer, tio kvinnor och tio män rekryterades som frivilliga deltagare. Deltagarna randomiserades för att träna antingen vänster eller höger ben. Träningsperioden var tio veckor (trettiofyra pass) av unilateral styrketräning i benpress och benspark, sexton deltagare uppfyllde kriterierna för inkludering. Två initiala familjäriseringspass hölls varefter träningen delades in i två typer av träning, dels konventionell styrketräning tre gånger i veckan (vecka 1-3, 5-7 och 9-10) och dels Blood Flow Restriction Training (BFRT) fem gånger i veckan (vecka 4 och 8). Före, efter och efter tjugo veckor testades one repetition maximum för båda benen i benpress och benspark samt att ultraljudsmätningar för muskeltjocklek utfördes.     Resultat    Den tio veckor långa träningsperioden resulterade i en signifikant ökning av den maximala styrkan för det otränade benet 18,9 % (16,6) (p &lt; 0,010) i benpressen och 6,7 % (3,7) (p &lt; 0,050) i bensparken. När jämförelser gjordes mellan könen så hade enbart män en signifikant ökning, 26,5 % (16,7) (p &lt; 0,010) i benpressen och 9,9 % (4,7) (p &lt; 0,050) i bensparken. Vi fann även att det var en signifikant skillnad mellan kvinnor och män på gruppnivå.   Jämförelser mellan dominant och icke-dominant ben visade att träning av det dominanta benet resulterade i en signifikant styrkeökning i både benpress 22 % (17,9) (p &lt; 0,010) och benspark 10,1 % (4,3) (p &lt; 0,050). Den maximala styrkan i det otränade benet påverkades inte signifikant av en viloperiod och en signifikant ökning i muskeltjocklek kunde ses i det otränade benet i MP50 4,7 % (1,3) (p &lt; 0,010)    Konklusion    Slutsatserna är att en tio veckors unilateral styrketräningsintervention resulterar i en CE effekt hos män men inte hos kvinnor, och att denna typ av träning kan resultera i en ökad muskeltjocklek i det otränade benet. Våra fynd styrker att träning av den dominanta lemmen har större effekt på CE. Slutligen drar vi slutsatsen att en tjugo veckors viloperiod inte påverkar CE-styrkan.  

Cross Education; : The effect of 10 weeks of unilateral resistance training on strength and hypertrophy

Abstract    Aim    The main purpose of this study was to investigate Cross Education (CE), and how gender, detraining and leg dominance affects CE in previously untrained subjects when conducting a unilateral resistance training program. We also investigated if unilateral resistance training can give a hypertrophic response.    Method   Twenty healthy previously untrained individuals, 10 females and 10 males, were recruited as volunteer participants. The participants were randomly assigned to train either left or right leg. The training intervention was 10 weeks (34 sessions) of unilateral resistance training in the leg press and leg extension, sixteen of the participants fulfilled the criteria for inclusion. After two initial familiarization the participants trained conventional resistance training three times a week (week 1-3, 5-7 and 9-10) and Blood Flow Restriction Training (BFRT) five times a week (week 4 and 8). One repetition maximum for both legs in the leg press and leg extension was tested pre-, post and post20 to the training intervention as well as ultrasound measurements of muscle thickness.   Results    The ten-week training period resulted in a significant increase of maximal strength for the untrained leg 18,9 %, (16,6) (p &lt; 0,01) in the leg press and 6,7 %, (3,7) (p &lt; 0,05) in the leg extension. When comparisons between gender were made only men had a significant increase 26,5 %, (16,7) (p &lt; 0,01) in the leg press and 9,9 %, (4,7) (p &lt; 0,05) in the leg extension. Also, we saw a significant difference between women and men on a group level. Comparisons of dominant vs non-dominant leg showed that training the dominant leg resulted in a significant increase of maximal strength in the untrained leg in both the leg press 22 %, (17,9) (p &lt; 0,01) and leg extension 10,1 %, (4,3) (p &lt; 0,05). The maximal strength in the untrained leg was not significantly altered by the detraining period and a significant increase of muscle thickness could be seen in the untrained leg at MP50 4,7 %, (1,3) (p &lt; 0,01).   Conclusion    The conclusions are that a ten week unilateral resistance training intervention results in a CE effect for men but not for women and that this type of training also can result in an increased muscle thickness in the untrained leg. Our findings also supports that training the dominant limb has superior effect on achieving a CE effect. Lastly we conclude that a twenty week detraining period did not affect the CE achieved strength.   Abstrakt    Syfte     Studiens huvudsakliga syfte var att undersöka Cross Education (CE) och hur kön, viloperiod och ben-dominans påverkar CE hos otränade individer när man undergår ett unilateralt styrketräningsprogram. Vi undersökte även om ett unilateral styrketräning kunde ge ett hypertrofisvar.    Metod    Tjugo friska otränade och för närvarande inaktiva individer, tio kvinnor och tio män rekryterades som frivilliga deltagare. Deltagarna randomiserades för att träna antingen vänster eller höger ben. Träningsperioden var tio veckor (trettiofyra pass) av unilateral styrketräning i benpress och benspark, sexton deltagare uppfyllde kriterierna för inkludering. Två initiala familjäriseringspass hölls varefter träningen delades in i två typer av träning, dels konventionell styrketräning tre gånger i veckan (vecka 1-3, 5-7 och 9-10) och dels Blood Flow Restriction Training (BFRT) fem gånger i veckan (vecka 4 och 8). Före, efter och efter tjugo veckor testades one repetition maximum för båda benen i benpress och benspark samt att ultraljudsmätningar för muskeltjocklek utfördes.     Resultat    Den tio veckor långa träningsperioden resulterade i en signifikant ökning av den maximala styrkan för det otränade benet 18,9 % (16,6) (p &lt; 0,010) i benpressen och 6,7 % (3,7) (p &lt; 0,050) i bensparken. När jämförelser gjordes mellan könen så hade enbart män en signifikant ökning, 26,5 % (16,7) (p &lt; 0,010) i benpressen och 9,9 % (4,7) (p &lt; 0,050) i bensparken. Vi fann även att det var en signifikant skillnad mellan kvinnor och män på gruppnivå.   Jämförelser mellan dominant och icke-dominant ben visade att träning av det dominanta benet resulterade i en signifikant styrkeökning i både benpress 22 % (17,9) (p &lt; 0,010) och benspark 10,1 % (4,3) (p &lt; 0,050). Den maximala styrkan i det otränade benet påverkades inte signifikant av en viloperiod och en signifikant ökning i muskeltjocklek kunde ses i det otränade benet i MP50 4,7 % (1,3) (p &lt; 0,010)    Konklusion    Slutsatserna är att en tio veckors unilateral styrketräningsintervention resulterar i en CE effekt hos män men inte hos kvinnor, och att denna typ av träning kan resultera i en ökad muskeltjocklek i det otränade benet. Våra fynd styrker att träning av den dominanta lemmen har större effekt på CE. Slutligen drar vi slutsatsen att en tjugo veckors viloperiod inte påverkar CE-styrkan.