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1.	Aare, Sudhakar, et al. (author) Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model 2013 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 45:8, s. 312-320 Journal article (peer-reviewed)abstract Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator, and a decreased quality of life post-ICU. The mechanisms underlying limb muscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization, and systemic administration of corticosteroids (CS). These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for 5 days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes according to microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional upregulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response, cytoskeletal, sarcomeric, and heat shock protein, as well as protein synthesis at the translational level, appears to play an additive deleterious role for the limb muscle weakness in immobilized ICU patients.
2.	Aare, Sudhakar, et al. (author) Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model 2011 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 43:24, s. 1334-1350 Journal article (peer-reviewed)abstract Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.
3.	Aare, Sudhakar, et al. (author) The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model 2012 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 44:18, s. 865-877 Journal article (peer-reviewed)abstract Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.
4.	Akerblad, P, et al. (author) Gene expression analysis suggests that EBF-1 and PPAR gamma 2 induce adipogenesis of NIH-3T3 cells with similar efficiency and kinetics 2005 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 23:2, s. 206-216 Journal article (peer-reviewed)abstract Differentiation of multipotent mesenchymal stem cells into lipid-accumulating adipocytes is a physiological process induced by transcription factors in combination with hormonal stimulation. We have used Affymetrix microarrays to compare the adipogenic differentiation pathways of NIH-3T3 fibroblasts induced to undergo in vitro differentiation by ectopic expression of early B cell factor (EBF)-1 or peroxisome proliferator-activated receptor (PPAR)gamma 2. These experiments revealed that commitment to the adipogenic pathway in the NIH-3T3 cells was not reflected in gene expression until 4 days after induction of differentiation. Furthermore, gene expression patterns at the earlier time points after stimulation indicated that EBF-1 and PPAR gamma 2 induced different sets of genes, while the similarities increased upon differentiation, and that several genes linked to adipocyte differentiation were also transiently induced in the vector-transduced cells. These data suggest that the initial activation of genes associated with adipocyte development is independent of commitment to the adipogenic pathway and that EBF-1 and PPAR gamma 2 induce adipocyte differentiation with comparable kinetics and efficiency.
5.	Albinsson, Sebastian, et al. (author) Can microRNAs control vascular smooth muscle phenotypic modulation and the response to injury? 2010 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; okt Journal article (peer-reviewed)abstract Vascular smooth muscle cell (VSMC) migration and proliferation are critical events in vascular proliferative diseases. Recent studies have established micro-RNAs (miRNAs) as important mediators for the modulation of VSMC phenotype by targeting transcription factors and the cytoskeleton, which act as molecular switches for VSMC differentiation. The importance of miRNAs for VSMC development, differentiation and function is evident by the fact that loss of the miRNA processing enzyme Dicer in VSMCs results in embryonic lethality due to severe vascular abnormalities. In addition, a role of specific miRNAs for neointimal hyperplasia following vascular injury has been reported which provides interesting possibilities for future therapeutical targets against vascular disease. Herein, we summarize recent advances regarding the role of miRNAs in VSMC phenotype modulation and response to injury.
6.	Asp, Julia, 1973, et al. (author) Comparison of human cardiac gene expression profiles in paired samples of right atrium and left ventricle collected in vivo 2012 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 44:1, s. 89-98 Journal article (peer-reviewed)abstract Studies of expressed genes in human heart provide insight into both physiological and pathophysiological mechanisms. This is of importance for extended understanding of cardiac function as well as development of new therapeutic drugs. Heart tissue for gene expression studies is generally hard to obtain, particularly from the ventricles. Since different parts of the heart have different functions, expression profiles should likely differ between these parts. The aim of the study was therefore to compare the global gene expression in cardiac tissue from the more accessible auricula of the right atrium to expression in tissue from the left ventricle. Tissue samples were collected from five men undergoing aortic valve replacement or coronary artery bypass grafting. Global gene expression analysis identified 542 genes as differentially expressed between the samples extracted from these two locations, corresponding to similar to 2% of the genes covered by the microarray; 416 genes were identified as abundantly expressed in right atrium, and 126 genes were abundantly expressed in left ventricle. Further analysis of the differentially expressed genes according to available annotations, information from curated pathways and known protein interactions, showed that genes with higher expression in the ventricle were mainly associated with contractile work of the heart. Transcription in biopsies from the auricula of the right atrium on the other hand indicated a wider area of functions, including immunity and defense. In conclusion, our results suggest that biopsies from the auricula of the right atrium may be suitable for various genetic studies, but not studies directly related to muscle work.
7.	Banduseela, Varuna C., et al. (author) Gene expression and muscle fiber function in a porcine ICU model 2009 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 39:3, s. 141-159 Journal article (peer-reviewed)abstract Skeletal muscle wasting and impaired muscle function in response to mechanical ventilation and immobilization in intensive care unit (ICU) patients are clinically challenging partly due to 1) the poorly understood intricate cellular and molecular networks and 2) the unavailability of an animal model mimicking this condition. By employing a unique porcine model mimicking the conditions in the ICU with long-term mechanical ventilation and immobilization, we have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a 5-day period. Among the differentially regulated transcripts, extracellular matrix, energy metabolism, sarcomeric and LIM protein mRNA levels were downregulated, while ubiquitin proteasome system, cathepsins, oxidative stress responsive genes and heat shock proteins (HSP) mRNAs were upregulated. Despite 5 days of immobilization and mechanical ventilation single muscle fiber cross-sectional areas as well as the maximum force generating capacity at the single muscle fiber level were preserved. It is proposed that HSP induction in skeletal muscle is an inherent, primary, but temporary protective mechanism against protein degradation. To our knowledge, this is the first study that isolates the effect of immobilization and mechanical ventilation in an ICU condition from various other cofactors.
8.	Banduseela, Varuna, et al. (author) Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle 2013 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 45:12, s. 477-486 Journal article (peer-reviewed)abstract Critical illness myopathy (CIM) is characterized by a preferential loss of the motor protein myosin, muscle wasting, and impaired muscle function in critically ill intensive care unit (ICU) patients. CIM is associated with severe morbidity and mortality and has a significant negative socioeconomic effect. Neuromuscular blocking agents, corticosteroids, sepsis, mechanical ventilation, and immobilization have been implicated as important risk factors, but the causal relationship between CIM and the risk factors has not been established. A porcine ICU model has been used to determine the immediate molecular and cellular cascades that may contribute to the pathogenesis prior to myosin loss and extensive muscle wasting. Expression profiles have been compared between pigs exposed to the ICU interventions, i.e., mechanically ventilated, sedated, and immobilized for 5 days, with pigs exposed to critical illness interventions, i.e., neuromuscular blocking agents, corticosteroids, and induced sepsis in addition to the ICU interventions for 5 days. Impaired autophagy as well as impaired chaperone expression and protein synthesis were observed in the skeletal muscle in response to critical illness interventions. A novel finding in this study is impaired core autophagy machinery in response to critical illness interventions, which when in concert with downregulated chaperone expression and protein synthesis may collectively affect the proteostasis in skeletal muscle and may exacerbate the disease progression in CIM.
9.	Becirovic Agic, Mediha, et al. (author) Quantitative trait loci associated with angiotensin II and high-salt diet induced acute decompensated heart failure in Balb/CJ mice 2019 In: Physiological Genomics. - : AMER PHYSIOLOGICAL SOC. - 1094-8341 .- 1531-2267. ; 51:7, s. 279-289 Journal article (peer-reviewed)abstract Genetic background of different mouse strains determines their susceptibility to disease. We have previously shown that Balb/CJ and C57BL/6J mice develop cardiac hypertrophy to the same degree when treated with a combination of angiotensin II and high-salt diet (ANG II+ Salt). but only Balb/CJ show impaired cardiac function associated with edema development and substantial mortality. We hypothesized that the different response to ANG II +Salt is due to the different genetic backgrounds of Balb/CJ and C57BL/6J. To address this we performed quantitative trait locus (QTL) mapping of second filial generation (F2) of mice derived from a backcross between Balb/CJ and first filial generation (Fl) of mice. Cardiac function was measured with echocardiography, glomerular filtration rate using FITC-inulin clearance, fluid and electrolyte balance in metabolic cages, and blood pressure with tail-cuff at baseline and on the fourth day of treatment with ANG II+Salt. A total of nine QTLs were found to be linked to different phenotypes in ANG II + Salt-treated F2 mice. A QTL on chromosome 3 was linked to cardiac output. and a QTL on chromosome 12 was linked to isovolumic relaxation time. QTLs on chromosome 2 and 3 were linked to urine excretion and sodium excretion. Eight genes located at the different QTLs contained coding nonsynonymous SNPs published in the mouse genome database that differ between Balb/CJ and C57BL/6J. In conclusion. ANG II+Salt-induced acute decompensation in Balb/CJ is genetically linked to several QTLs, indicating a multifaceted phenotype. The present study identified potential candidate genes that may represent important pathways in acute decompensated heart failure.
10.	Blackwell, TA, et al. (author) Transcriptomic analysis of the development of skeletal muscle atrophy in cancer-cachexia in tumor-bearing mice 2018 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 50:12, s. 1071-1082 Journal article (peer-reviewed)abstract Cancer-cachexia (CC) is a wasting condition directly responsible for 20–40% of cancer-related deaths. The mechanisms controlling development of CC-induced muscle wasting are not fully elucidated. Most investigations focus on the postcachectic state and do not examine progression of the condition. We recently demonstrated mitochondrial degenerations precede muscle wasting in time course progression of CC. However, the extent of muscle perturbations before wasting in CC is unknown. Therefore, we performed global gene expression analysis in CC-induced muscle wasting to enhance understanding of intramuscular perturbations across the development of CC. Lewis lung carcinoma (LLC) was injected into the hind-flank of C57BL6/J mice at 8 wk of age with tumor allowed to develop for 1, 2, 3, or 4 wk and compared with PBS-injected control. Muscle wasting was evident at 4 wk LLC. RNA sequencing of gastrocnemius muscle samples showed widespread alterations in LLC compared with PBS animals with largest differences seen in 4 wk LLC, suggesting extensive transcriptomic alterations concurrent to muscle wasting. Commonly altered pathways included: mitochondrial dysfunction and protein ubiquitination, along with other less studied processes in this condition regulating transcription/translation and cytoskeletal structure. Current findings present novel evidence of transcriptomic shifts and altered cellular pathways in CC-induced muscle wasting.
11.	Blizard, David A., et al. (author) Blood pressure and heart rate QTL in mice of the B6/D2 lineage sex differences and environmental influences 2009 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 36:3, s. 158-166 Journal article (peer-reviewed)abstract A quantitative trait locus (QTL) approach was used to define the genetic architecture underlying variation in systolic blood pressure (SBP) and heart rate (HR), measured indirectly on seven occasions by the tail cuff procedure. The tests were conducted in 395 F(2) adult mice (197 males, 198 females) derived from a cross of the C57BL/6J (B6) and DBA/2J (D2) strains and in 22 BXD recombinant-inbred (RI) strains. Interval mapping of F(2) data for the first 5 days of measurement nominated one statistically significant and one suggestive QTL for SBP on chromosomes (Chr) 4 and 14, respectively, and two statistically significant QTL for HR on Chr 1 (which was specific to female mice) and Chr 5. New suggestive QTL emerged for SBP on Chr 3 (female-specific) and 8 and for HR on Chr 11 for measurements recorded several weeks after mice had undergone stressful blood sampling procedures. The two statistically significant HR QTL were confirmed by analyses of BXD RI strain means. Male and female F(2) mice did not differ in SBP or HR but RI strain analyses showed pronounced strain-by-sex interactions and a negative genetic correlation between the two measures in both sexes. Evidence for a role for mitochondrial DNA was found for both HR and SBP. QTL for HR and SBP may differ in males and females and may be sensitive to different environmental contexts.
12.	Chaillou, Thomas, 1985-, et al. (author) Pitfalls in target mRNA quantification for real-time quantitative RT-PCR in overload-induced skeletal muscle hypertrophy 2011 In: Physiological Genomics. - Bethesda, USA : American Physiological Society. - 1094-8341 .- 1531-2267. ; 43:4, s. 228-235 Journal article (peer-reviewed)abstract Quantifying target mRNA using real-time quantitative reverse transcription-polymerase chain reaction requires an accurate normalization method. Determination of normalization factors (NFs) based on validated reference genes according to their relative stability is currently the best standard method in most usual situations. This method controls for technical errors, but its physiological relevance requires constant NF values for a fixed weight of tissue. In the functional overload model, the increase in the total RNA concentration must be considered in determining the NF values. Here, we pointed out a limitation of the classical geNorm-derived normalization. geNorm software selected reference genes despite that the NF values extensively varied under experiment. Only the NF values calculated from four intentionally selected genes were constant between groups. However, a normalization based on these genes is questionable. Indeed, three out of four genes belong to the same functional class (negative regulator of muscle mass), and their use is physiological nonsense in a hypertrophic model. Thus, we proposed guidelines for optimizing target mRNA normalization and quantification, useful in models of muscle mass modulation. In our study, the normalization method by multiple reference genes was not appropriate to compare target mRNA levels between overloaded and control muscles. A solution should be to use an absolute quantification of target mRNAs per unit weight of tissue, without any internal normalization. Even if the technical variations will stay present as a part of the intergroup variations, leading to less statistical power, we consider this method acceptable because it will not generate misleading results.
13.	Ek, Weronica, et al. (author) Genetic analysis of metabolic traits in an intercross between body weight-selected chicken lines 2010 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 42:1, s. 20-22 Journal article (peer-reviewed)abstract A network of four interacting loci has been reported previously to influence growth in two lines of chickens divergently selected for body weight at 56 days of age. Located on chromosomes 3 (Growth4), 4 (Growth6), 7 (Growth9), and 20 (Growth12), they explained nearly half of the difference in body weight at selection age between the two lines. The original study reported effects on body weight and fat deposition, but no attempts were made to explore the effects of the network on other phenotypes measured in the F(2) population. In this study we conducted further analyses to evaluate the specific effects of the four-locus network on other metabolic traits as well as refining results from the original study by including a larger number of genetic markers in the quantitative trait locus (QTL) regions. We confirm the previously described effect of the epistatic network on body weight and show that the network increases the total amount of muscle and fat as well as the weight of the internal organs. The network as a whole did not change the relative content of any studied organs or tissues in the body. There was, however, a significant interaction between the loci on chromosomes 3 and 7 that changed the relative proportion of abdominal fat and breast muscle in the chicken by increasing abdominal fat weight without a corresponding increase in muscle mass.
14.	Eriksson, Mikael, et al. (author) Uromodulin in sepsis and severe pneumonia : a two-sample Mendelian randomization study 2024 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 56:5, s. 409-416 Journal article (peer-reviewed)abstract The outcome for patients with sepsis-associated acute kidney injury in the intensive care unit (ICU) remains poor. Low serum uromodulin (sUMOD) protein levels have been proposed as a causal mediator of this effect. We investigated the effect of different levels of sUMOD on the risk of sepsis and severe pneumonia and outcomes in these conditions. A two-sample Mendelian randomization (MR) study was performed. Single-nucleotide polymorphisms (SNPs) associated with increased levels of sUMOD were identified and used as instrumental variables for association with outcomes. Data from different cohorts were combined based on disease severity and meta-analyzed. Five SNPs associated with increased sUMOD levels were identified and tested in six datasets from two biobanks. There was no protective effect of increased levels of sUMOD on the risk of sepsis [two cohorts, odds ratio (OR) 0.99 (95% confidence interval 0.95-1.03), P = 0.698, and OR 0.95 (0.91-1.00), P = 0.060, respectively], risk of sepsis requiring ICU admission [OR 1.04 (0.93-1.16), P = 0.467], ICU mortality in sepsis [OR 1.00 (0.74-1.37), P = 0.987], risk of pneumonia requiring ICU admission [OR 1.05 (0.98-1.14), P = 0.181], or ICU mortality in pneumonia [OR 1.17 (0.98-1.39), P = 0.079]. Meta-analysis of hospital-admitted and ICU-admitted patients separately yielded similar results [OR 0.98 (0.95-1.01), P = 0.23, and OR 1.05 (0.99-1.12), P = 0.86, respectively]. Among patients with sepsis and severe pneumonia, there was no protective effect of different levels of sUMOD. Results were consistent regardless of geographic origins and not modified by disease severity.
15.	Fischer, M Dominik, et al. (author) Definition of the unique human extraocular muscle allotype by expression profiling. 2005 In: Physiol Genomics. - : American Physiological Society. - 1531-2267. ; 22:3, s. 283-91 Journal article (peer-reviewed)abstract The extraocular muscles (EOMs) are a unique group of specialized muscles that are anatomically and physiologically distinct from other skeletal muscles. Perhaps the most striking characteristic of the EOMs is their differential sensitivity to disease. EOMs are spared in Duchenne's muscular dystrophy (DMD) despite widespread involvement of other skeletal muscles. Conversely, they are early and prominent targets in myasthenia gravis and mitochondrial myopathies. It is unclear how EOMs achieve such specialization or a differential response to diseases; however, this has been attributed to a unique, group-specific pattern of gene expression or "allotype." To begin to address these issues as well as define the human EOM allotype, we analyzed the human EOM transcriptome using oligonucleotide-based expression profiling. Three hundred thirty-eight genes were found to be differentially expressed in EOM compared with quadriceps femoris limb muscle, using a twofold cutoff. Functional characterization revealed expression patterns corresponding to known metabolic and structural properties of EOMs such as expression of EOM-specific myosin heavy chain (MYH13) and high neural, vascular, and mitochondrial content, suggesting that the profiling was sensitive and specific. Genes related to myogenesis, stem cells, and apoptosis were detected at high levels in normal human EOMs, suggesting that efficient and continuous regeneration and/or myogenesis may be a mechanism by which the EOMs remain clinically and pathologically spared in diseases such as DMD. Taken together, this study provides insight into how human EOMs achieve their unique structural, metabolic, and pathophysiological properties.
16.	Fischer, M Dominik, et al. (author) Expression profiling reveals metabolic and structural components of extraocular muscles 2002 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 9:2, s. 71-84 Journal article (peer-reviewed)abstract The extraocular muscles (EOM) are anatomically and physiologically distinct from other skeletal muscles. EOM are preferentially affected in mitochondrial myopathies, but spared in Duchenne's muscular dystrophy. The anatomical and pathophysiological properties of EOM have been attributed to their unique molecular makeup: an allotype. We used expression profiling to define molecular features of the EOM allotype. We found 346 differentially expressed genes in rat EOM compared with tibialis anterior, based on a twofold difference cutoff. Genes required for efficient, fatigue-resistant, oxidative metabolism were increased in EOM, whereas genes for glycogen metabolism were decreased. EOM also showed increased expression of genes related to structural components of EOM such as vessels, nerves, mitochondria, and neuromuscular junctions. Additionally, genes related to specialized functional roles of EOM such as the embryonic and EOM-specific myosin heavy chains and genes for muscle growth, development, and/or regeneration were increased. The EOM expression profile was validated using biochemical, structural, and molecular methods. Characterization of the EOM expression profile begins to define gene transcription patterns associated with the unique anatomical, metabolic, and pathophysiological properties of EOM.
17.	Fuller, Jessica, et al. (author) Genetic Dissection Reveals Diabetes Loci Proximal to the Gimap5 Lymphopenia Gene. 2009 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 38, s. 89-97 Journal article (peer-reviewed)abstract Congenic DRF.(f/f) rats are protected from type 1 diabetes (T1D) by 34 Mb of F344 DNA introgressed proximal to the Gimap5 lymphopenia gene. To dissect the genetic factor(s) that confer protection from T1D in the DRF.(f/f) rat line, DRF.(f/f) rats were crossed to inbred BBDR or DR.(lyp/lyp) rats to generate congenic sublines that were genotyped, monitored for T1D and positional candidate genes sequenced. All (100%) DR.(lyp/lyp) rats developed T1D by 83 days of age. Reduction of the DRF.(f/f) F344 DNA fragment by 26 Mb (42.52 Mb-68.51 Mb) retained complete T1D protection. Further dissection revealed that a 2 Mb interval of F344 DNA (67.41-70.17 Mb) (Region 1) resulted in 47% protection and significantly delayed onset (p<0.001 compared to DR.(lyp/lyp)). Retaining <1 Mb of F344 DNA at the distal end (76.49-76.83 Mb) (Region 2) resulted in 28% protection and also delayed onset (p<0.001 compared to DR.(lyp/lyp)). Comparative analysis of diabetes frequency in the DRF.(f/f) congenic sublines further refined the RNO4 Region 1 interval to approximately 670 Kb and Region 2 to the 340 Kb proximal to Gimap5. All congenic DRF.(f/f) sublines were prone to low-grade pancreatic mononuclear cell infiltration around ducts and vessels but less than 20% of islets in non-diabetic rats showed islet infiltration. Coding sequence analysis revealed TCR Vbeta 8E, 12 and 13 as candidate genes in Region 1 and Znf467 and Atp6v0e2 as candidate genes in Region 2. Our results show that spontaneous T1D is controlled by at least two genetic loci 7 Mb apart on rat chromosome 4. Key words: Type 1 diabetes, BB rat, T cell receptor, autoimmune.
18.	Geahlen, J. H., et al. (author) Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of GKN3 2013 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 45:15, s. 667-683 Journal article (peer-reviewed)abstract In a screen for genes expressed specifically in gastric mucous neck cells, we identified GKN3, the recently discovered third member of the gastrokine family. We present confirmatory mouse data and novel porcine data showing that mouse GKN3 expression is confined to mucous cells of the corpus neck and antrum base and is prominently expressed in metaplastic lesions. GKN3 was proposed originally to be expressed in some human populations and a pseudogene in others. To investigate that hypothesis, we studied human GKN3 evolution in the context of its paralogous genomic neighbors, GKN1 and GKN2. Haplotype analysis revealed that GKN3 mimics GKN2 in patterns of exonic SNP allocation, whereas GKN1 appeared to be more stringently selected. GKN3 showed signatures of both directional selection and population based selective sweeps in humans. One such selective sweep includes SNP rs10187256, originally identified as an ancestral tryptophan to premature STOP codon mutation. The derived (nonancestral) allele went to fixation in Asia. We show that another SNP, rs75578132, identified 5 bp downstream of rs10187256, exhibits a second selective sweep in almost all Europeans, some Latinos, and some Africans, possibly resulting from a reintroduction of European genes during African colonization. Finally, we identify a mutation that would destroy the splice donor site in the putative exon3-intron3 boundary, which occurs in all human genomes examined to date. Our results highlight a stomach-specific human genetic locus, which has undergone various selective sweeps across European, Asian, and African populations and thus reflects geographic and ethnic patterns in genome evolution.
19.	Ghosheh, Nidal, et al. (author) Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue 2017 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 49:8, s. 430-446 Journal article (peer-reviewed)abstract Hepatocytes derived from human pluripotent stem cells (hPSC-HEP) have the potential to replace presently used hepatocyte sources applied in liver disease treatment and models of drug discovery and development. Established hepatocyte differentiation protocols are effective and generate hepatocytes, which recapitulate some key features of their in vivo counterparts. However, generating mature hPSC-HEP remains a challenge. In this study, we applied transcriptomics to investigate the progress of in vitro hepatic differentiation of hPSCs at the developmental stages, definitive endoderm, hepatoblasts, early hPSC-HEP, and mature hPSC-HEP, to identify functional targets that enhance efficient hepatocyte differentiation. Using functional annotation, pathway and protein interaction network analyses, we observed the grouping of differentially expressed genes in specific clusters representing typical developmental stages of hepatic differentiation. In addition, we identified hub proteins and modules that were involved in the cell cycle process at early differentiation stages. We also identified hub proteins that differed in expression levels between hPSC-HEP and the liver tissue controls. Moreover, we identified a module of genes that were expressed at higher levels in the liver tissue samples than in the hPSC-HEP. Considering that hub proteins and modules generally are essential and have important roles in the protein-protein interactions, further investigation of these genes and their regulators may contribute to a better understanding of the differentiation process. This may suggest novel target pathways and molecules for improvement of hPSC-HEP functionality, having the potential to finally bring this technology to a wider use.
20.	Gomez-Gallego, F, et al. (author) Are elite endurance athletes genetically predisposed to lower disease risk? 2010 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 41:1, s. 82-90 Journal article (peer-reviewed)abstract We compared a polygenic profile that combined 33 disease risk-related mutations and polymorphisms among nonathletic healthy control subjects and elite endurance athletes. The study sample comprised 100 healthy Spanish male nonathletic (sedentary) control subjects and 100 male elite endurance athletes. We analyzed 33 disease risk-related mutations and polymorphisms. We computed a health-related total genotype score (TGS, 0–100) from the accumulated combination of the 33 variants. We did not observe significant differences in genotype or allele distributions among groups, except for the rs4994 polymorphism ( P < 0.001). The computed health-related TGS was similar among groups (23.8 ± 1.0 vs. 24.2 ± 0.8 in control subjects and athletes, respectively; P = 0.553). Similar results were obtained when computing specific TGSs for each main disease category (cardiovascular disease and cancer). We observed no evidence that male elite endurance athletes are genetically predisposed to have lower disease risk than matched nonathletic control subjects.
21.	Greenwood, Tiffany A, et al. (author) Genome-wide linkage analysis of chromogranin B expression in the CEPH pedigrees : implications for exocytotic sympathochromaffin secretion in humans. 2004 In: Physiol Genomics. - 1531-2267. ; 18:1, s. 119-27 Journal article (other academic/artistic)
22.	Greenwood, Tiffany A, et al. (author) Pleiotropic effects of novel trans-acting loci influencing human sympathochromaffin secretion. 2006 In: Physiol Genomics. - 1531-2267. ; 25:3, s. 470-9 Journal article (peer-reviewed)
23.	Grundberg, Elin, et al. (author) Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells 2008 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 33:3, s. 301-11 Journal article (peer-reviewed)abstract Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HObs) from bone explants makes them a lucrative model for studying molecular physiology of bone turnover, for discovering novel anabolic therapeutics, and for mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs, and to date no studies have been conducted to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks with genomewide expression profiling in resting and bone morphogenic protein (BMP)-2- and dexamethasone-induced cells. In addition, we compared HOb gene expression with publicly available samples from the Gene Expression Omnibus. Our data show a vast number of genes and networks expressed predominantly in HObs compared with closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs (P = 0.003) and included the binding proteins (IGFBP-1, -2, -5) and IGF-II and its receptor. Another HOb-specific expression pattern included leptin and its receptor (P < 10(-8)). Furthermore, after stimulation of HObs with BMP-2 or dexamethasone, the expression of several interesting genes and pathways was observed. For instance, our data support the role of peripheral leptin signaling in bone cell function. In conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs. This resource will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.
24.	Holmgren, Gustav, 1983-, et al. (author) Identification of stable reference genes in differentiating human pluripotent stem cells 2015 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 47:6, s. 232-239 Journal article (peer-reviewed)abstract Reference genes, often referred to as housekeeping genes (HKGs), are frequently used to normalize gene expression data based on the assumption that they are expressed at a constant level in the cells. However, several studies have shown that there may be a large variability in the gene expression levels of HKGs in various cell types. In a previous study, employing human embryonic stem cells (hESCs) subjected to spontaneous differentiation, we observed that the expression of commonly used HKG varied to a degree that rendered them inappropriate to use as reference genes under those experimental settings. Here we present a substantially extended study of the HKG signature in human pluripotent stem cells (hPSC), including nine global gene expression datasets from both hESC and human induced pluripotent stem cells (hiPSCs), obtained during directed differentiation towards endoderm-, mesoderm-, and ectoderm derivatives. Sets of stably expressed genes were compiled and a handful of genes (e.g., EID2, ZNF324B, CAPN10, and RABEP2) were identified as generally applicable reference genes in hPSCs across all cell lines and experimental conditions. The stability in gene expression profiles was confirmed by quantitative PCR (RT-qPCR) analysis. Taken together, the current results suggest that differentiating hPSCs have a distinct HKG signature, which in some aspects is different from somatic cell types, and underscore the necessity to validate the stability of reference genes under the actual experimental setup used. In addition, the novel putative HKGs identified in this study can preferentially be used for normalization of gene expression data obtained from differentiating hPSCs.
25.	Hultström, Michael, et al. (author) Collagen-binding proteins in age-dependent changes in renal collagen turnover : microarray analysis of mRNA expression 2012 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 44:10, s. 576-586 Journal article (peer-reviewed)abstract Aging is associated with progressive structural and functional deterioration of the kidney. Among the morphological changes associated with renal aging is an accumulation of extracellular matrix (ECM) in the glomeruli and tubuloinsterstitium, which may ultimately lead to the development of renal fibrosis. The mechanisms governing the regulation of ECM metabolism during renal aging are only incompletely defined. We present data from a genome-wide mRNA expression study on renal tissue from 90 wk old male Wistar rats and 10 wk old controls using Illumina BeadArray cDNA microarray. Regulation of candidate gene products was verified by real-time PCR. Morphological changes were evaluated by routine histological methods. Activated fibroblasts were identified by their expression of alpha-smooth muscle actin and collagen I. Morphological analysis demonstrated an expansion of the tubulointerstitial compartment with increased amounts of fibrous collagen but no overt glomerular or tubular damage in the aged rats. Activated fibroblasts were readily detectable in the adventitial layer of large renal vessels in controls and were not found in the old animals. In agreement with this finding, gene expression analysis revealed significant downregulation of collagen I mRNA along with numerous other ECM components. Concomitantly, collagen-stabilizing proteins were induced, whereas matrix metalloproteinase 9, an enzyme involved in collagen breakdown, was reduced. In conclusion, our results suggest that ECM expansion during renal aging results from an augmented stabilization in conjunction with a reduced breakdown of collagen fibers. Collagen stabilizing proteins may be essential for the control of renal ECM turnover and the pathogenesis of kidney fibrosis.
26.	Hultström, Michael, 1978-, et al. (author) Comparison of acute kidney injury of different aetiology reveals in-common mechanisms of tissue damage 2018 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 50:3, s. 127-141 Research review (peer-reviewed)abstract Acute kidney injury (AKI) is a syndrome of reduced glomerular filtration rate (GFR) and urine production caused by a number of different diseases. It is associated with renal tissue damage. This tissue damage can cause tubular atrophy and interstitial fibrosis that leads to nephron loss and progression of chronic kidney disease (CKD). This review describes the in-common mechanisms behind tissue damage in AKI caused by different underlying diseases. Comparing six high-quality microarray studies of renal gene expression after AKI in disease models (gram-negative sepsis, gram-positive sepsis, ischemia-reperfusion, malignant hypertension, rhabdomyolysis and cisplatin toxicity) identified 5254 differentially expressed genes in at least one of the AKI models. 66% of genes were only found in one model showing that there are unique features to AKI depending on the underlying disease. There were in-common features in the form of four genes that were differentially expressed in all six models, 49 in at least five, and 215 were in-common between at least four models. Gene ontology enrichment analysis could be broadly categorized into the injurious processes hypoxia, oxidative stress, and inflammation, as well as the cellular outcomes of cell death and tissue remodeling in the form of epithelial to mesenchymal transition (EMT). Pathway analysis showed that MYC is a central connection in the network of activated genes in-common to AKI, which suggests that it may be a central regulator of renal gene expression in tissue injury during AKI. The outlining of this molecular network may be useful for understanding progression from AKI to CKD.
27.	Hägg Samuelsson, Ulrika, 1973, et al. (author) Gene expression profile and aortic vessel distensibility in voluntarily exercised spontaneously hypertensive rats: potential role of heat shock proteins 2005 In: Physiol Genomics. - 1531-2267 .- 1094-8341. ; 22:3, s. 319-26 Journal article (peer-reviewed)abstract Physical exercise is considered to be beneficial for cardiovascular health. Nevertheless, the underlying specific molecular mechanisms still remain unexplored. In this study, we aimed to investigate the effects of voluntary exercise on vascular mechanical properties and gene regulation patterns in spontaneously hypertensive rats. By using ultrasound biomicroscopy in an ex vivo perfusion chamber, we studied the distensibility of the thoracic aorta. Furthermore, exercise-induced gene regulation was studied in aortae, using microarray analysis and validated with real-time PCR. We found that distensibility was significantly improved in aortas from exercising compared with control rats (P < 0.0001). Exercising rats demonstrated a striking pattern of coordinated downregulation of genes belonging to the heat shock protein family. In conclusion, voluntary exercise leads to improved vessel wall distensibility and reduced gene expression of heat shock protein 60 and 70, which may indicate decreased oxidative stress in the aortic vascular wall.
28.	Ka, Sojeong, et al. (author) The expression of carnitine palmitoyl-CoA transferase-1B is influenced by a cis-acting eQTL in two chicken lines selected for high and low body weight 2013 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 45:9, s. 367-376 Journal article (peer-reviewed)abstract Carnitine palmitoyl-CoA transferase-1B is a mitochondrial enzyme in the fatty acid oxidation pathway. In a previous study, CPT1B was identified as differentially expressed in the hypothalamus of two lines of chickens established by long-term selection for high (HWS) or low (LWS) body weight. Mammals have three paralogs (CPT1a, b and c) while non-mammalian vertebrates only have two (CPT1A, B). CPT1A is expressed in liver and CPT1B in muscle. CPT1c is expressed in hypothalamus, where it regulates feeding and energy expenditure. We identified an intronic length polymorphism, fixed for different alleles in the two populations and mapped the hitherto missing CPT1B locus in the chicken genome assembly, to the distal tip of chromosome 1p. Based on molecular phylogeny and gene synteny we suggest that chicken CPT1B is pro-orthologous of the mammalian CPT1c. Chicken CPT1B was differentially expressed in both muscle and hypothalamus but in opposite directions: higher levels in hypothalamus but lower levels in muscle in the HWS than in the LWS line. Using an advanced inter-cross population of the lines, CPT1B expression was found to be influenced by a cis-acting expression quantitative trait locus in muscle. The increased expression in hypothalamus and reduced expression in muscle is consistent with an increased food intake in the HWS line and at the same time reduced fatty acid oxidation in muscle yielding a net accumulation of energy intake and storage. The altered expression of CPT1B in hypothalamus and peripheral tissue is likely to be a mechanism contributing to the remarkable difference between lines.
29.	Kararigas, G, et al. (author) Role of the estrogen/estrogen-receptor-beta axis in the genomic response to pressure overload-induced hypertrophy 2011 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 43:8, s. 438-446 Journal article (peer-reviewed)abstract Cardiac hypertrophy, the adaptive response of the heart to overload, is a major risk factor for heart failure and sudden death. Estrogen (E2) and estrogen receptor beta (ERbeta) offer protection against hypertrophy and in the transition to heart failure. However, the underlying pathways remain incompletely defined. We employed a publicly available microarray dataset of female wild-type (WT) and ERbeta knockout (BERKO) mice subjected to pressure overload-induced hypertrophy to perform a systematic investigation of the mechanisms involved in the protection conferred by the E2/ERbeta axis. We show that considerably more genes were modulated in response to pressure overload in BERKO mice than in WT mice. The majority of the identified candidates in BERKO mice were induced, while those in WT mice were repressed. Pathway analysis revealed a similar pattern. This study is the first to demonstrate that the lack of ERbeta led to a significant increase of inflammatory pathways. Mitochondrial bioenergetics- and oxidative stress-related pathways were also modulated. In conclusion, ERbeta acquires the role of gatekeeper of the genomic response of the heart to pressure overload-induced hypertrophy. This may offer the molecular explanation for its cardioprotective role. We consider the present study to be a useful resource and that it will contribute to downstream functional analysis and to the characterization of pathways with previously unknown role in hypertrophy.
30.	Karlsson, Göran, et al. (author) Gene expression profiling demonstrates that TGF-{beta}1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-{beta} signaling. 2005 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 21:3, s. 396-403 Journal article (peer-reviewed)abstract Transforming growth factor-β 1 (TGF-β) regulates cellular functions like proliferation, differentiation, and apoptosis. On the cell surface, TGF-β binds to receptor complexes consisting of TGF-β receptor type II (Tβ RII) and activin-like kinase receptor-5 (Alk5), and the downstream signaling is transduced by Smad and MAPK proteins. Recent data have shown that alternative receptor combinations aside from the classical pairing of Tβ RII/Alk5 can be relevant for TGF-β signaling. We have screened for alternative receptors for TGF-β and also for gene targets of TGF-β signaling, by performing functional assays and microarray analysis in murine embryonic fibroblast (MEF) cell lines lacking Alk5. Data from TGF-β-stimulated Alk5(-/-) cells show them to be completely unaffected by TGF-β. Additionally, 465 downstream targets of Alk5 signaling were identified when comparing Alk5(-/-) or TGF-β-stimulated Alk5(+/+) MEFs with unstimulated Alk5(+/+) cells. Our results demonstrate that, in MEFs, TGF-β signals exclusively through complexes involving Alk5, and give insight to its downstream effector genes.
31.	Lionikas, A., et al. (author) Genetic determinants of weight of fast- and slow-twitch skeletal muscle in 500-day-old mice of the C57BL/6J and DBA/2J lineage. 2005 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 21:2, s. 184-192 Journal article (peer-reviewed)abstract C57BL/6J (B6) and DBA/2J (D2) strains and two derivative populations, BXD recombinant inbred strains (BXD RIs) and B6D2F2, were used to explore genetic basis for variation in muscle weight at 500 days of age. In parallel with findings in 200-day-old mice (Lionikas A, Blizard DA, Vandenbergh DJ, Glover MG, Stout JT, Vogler GP, McClearn GE, and Larsson L. Physiol Genomics 16: 141-152, 2003), weight of slow-twitch soleus, mixed gastrocnemius, and fast-twitch tibialis anterior (TA) and extensor digitorum longus (EDL) muscles was 13-22% greater (P < 0.001) in B6 than in D2. Distribution of BXD RI strain means indicated that genetic influence on muscle weight (strain effect P < 0.001, all muscles) was of polygenic origin, and effect of genetic factors differed between males and females (strain-by-sex interaction: P < 0.01 for soleus, EDL; P < 0.05 for TA, gastrocnemius). Linkage analyses in B6D2F2 population identified QTL affecting muscle weight on Chr 1, 2, 6, and 9. Pleiotropic influences were observed for QTL on Chr 1 (soleus, TA), 2 (TA, EDL, gastrocnemius), and 9 (soleus, TA, EDL) and were not related to muscle type (fast/slow-twitch) or function (flexor/extensor). Effect of QTL on Chr 9 on soleus muscle was male specific. QTL on Chr 2 and 6 were previously observed at 200 days of age, whereas QTL on Chr 1 and 9 are novel muscle weight QTL. In summary, muscle weight in B6/D2 lineage is affected by a polygenic system that has variable influences at different ages, between males and females, and across muscles in a manner independent of muscle type.
32.	Mattsson, C. Mikael, et al. (author) Sports genetics moving forward - lessons learned from medical research 2016 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 48:3, s. 175-182 Journal article (peer-reviewed)abstract Sports genetics can take advantage of lessons learned from human disease genetics. By righting past mistakes and increasing scientific rigor, the breadth and depth of knowledge in the field can be magnified. We present an outline of challenges facing sports genetics in the light of experiences from medical research.Sports performance is complex, resulting from a combination of a wide variety of different traits and attributes. Improving sports genetics will foremost require analyses based on detailed phenotyping. In order to find widely valid, reproducible common variants associated with athletic phenotypes, study sample sizes must be dramatically increased. One paradox is that in order to confirm relevance, replications in specific populations must be undertaken. Family studies of athletes may facilitate the discovery of rare variants with large effects on athletic phenotypes. The complexity of the human genome, combined with the complexity of athletic phenotypes, will require additional metadata and biological validation to identify a comprehensive set of genes involved.Analysis of personal genetic and multiomic profiles contribute to our conceptualization of precision medicine; the same will be the case in precision sports science. In the refinement of sports genetics it is essential to evaluate similarities and differences between genders and among ethnicities. Sports genetics to date have been hampered by small sample sizes and biased methodology which can lead to erroneous associations and overestimation of effect sizes. Consequently, currently available genetic tests based on these inherently limited data cannot predict athletic performance with any accuracy.
33.	Mohamad Salleh, Suraya Binti (author) Gene coexpression network analysis reveals perirenal adipose tissue as an important target of prenatal malnutrition in sheep 2023 In: Physiological Genomics. - 1094-8341 .- 1531-2267. ; 55, s. 392-413 Journal article (peer-reviewed)abstract We have previously demonstrated that pre- and early postnatal malnutrition in sheep induced depot- and sex-specific changes in adipose morphological features, metabolic outcomes, and transcriptome in adulthood, with perirenal (PER) as the major target followed by subcutaneous (SUB) adipose tissue. We aimed to identify coexpressed and hub genes in SUB and PER to identify the underlying molecular mechanisms contributing to the early nutritional programming of adipose-related phenotypic outcomes. Transcriptomes of SUB and PER of male and female adult sheep with different pre- and early postnatal nutrition histories were used to construct networks of coexpressed genes likely to be functionally associated with pre- and early postnatal nutrition histories and phenotypic traits using weighted gene coexpression network analysis. The modules from PER showed enrichment of cell cycle regulation, gene expression, transmembrane transport, and metabolic processes associated with both sexes' prenatal nutrition. In SUB (only males), a module of enriched adenosine diphosphate metabolism and development correlated with prenatal nutrition. Sex-specific module enrichments were found in PER, such as chromatin modification in the male network but histone modification and mitochondria- and oxidative phosphorylation-related functions in the female network. These sex-specific modules correlated with prenatal nutrition and adipocyte size distribution patterns. Our results point to PER as a primary target of prenatal malnutrition compared to SUB, which played only a minor role. The prenatal programming of gene expression and cell cycle, potentially through epigenetic modifications, might be underlying mechanisms responsible for observed changes in PER expandability and adipocyte-size distribution patterns in adulthood in both sexes.
34.	Nilsen, A.J., et al. (author) Comparative hepatic gene expression profiling of rats treated with 1H,1H,2H,2H-heptadecafluorodecan-1-ol or with pentadecafluorooctanoic acid 2008 In: Physiol. Genomics. - : American Physiological Society. ; 34, s. 285-303 Journal article (peer-reviewed)abstract Pentadecafluorooctanoic acid is an established peroxisome proliferator. Little is known about effects of treatment with 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol, which is metabolized to pentadecafluorooctanoic acid. We compared effects of various dosages (3, 10, or 25 mg/kg body wt) of each of these compounds on hepatic gene expression in rats with microarrays. Microarray data were validated by real-time RT-PCR. Expression data were also correlated with hepatic activities of selected enzymes and with hepatic levels of pentadecafluorooctanoic acid and 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol. Pentadecafluorooctanoic acid caused the more powerful change in gene expression, in terms of both number of genes affected and extent of change in expression. Across the dosages used pentadecafluorooctanoic acid and 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol caused significant ( P ≤ 0.05) changes in expression for 441 and 105 genes, respectively. With 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol ∼38% of the 105 genes exhibited decreased expression with a dose of 25 mg/kg body wt, these genes also appearing less responsive to treatment at the lower dosages. Bioinformatic analysis suggested that these genes are associated with regulatory functions. With pentadecafluorooctanoic acid, increasing dosage up to 10 mg/kg body wt brought about progressive increase in expression of affected genes. Pathways analysis suggested similar effects of the two compounds on lipid and amino acid metabolism. Marked differences were also found, particularly with respect to effects on genes related to oxidative phosphorylation, oxidative metabolism, free radical scavenging, xenobiotic metabolism, and complement and coagulation cascades.
35.	Park, Hee-Bok, et al. (author) QTL analysis of body composition and metabolic traits in an intercross between chicken lines divergently selected for growth. 2006 In: Physiol Genomics. - 1531-2267. ; 25:2, s. 216-23 Journal article (other academic/artistic)
36.	Pastinen, Tomi, et al. (author) A survey of genetic and epigenetic variation affecting human gene expression. 2004 In: Physiol Genomics. - 1531-2267. ; 16:2, s. 184-93 Journal article (peer-reviewed)
37.	Sæther, JC, et al. (author) Small LDL subfractions are associated with coronary atherosclerosis despite no differences in conventional lipids 2023 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 55:1, s. 16-26 Journal article (peer-reviewed)abstract Lipoprotein subfractions currently represent a new source of cardiovascular disease (CVD) risk markers that may provide more information than conventional lipid measures. We aimed to investigate whether lipoprotein subfractions are associated with coronary atherosclerosis in patients without prior known CVD. Fasting serum samples from 60 patients with suspected coronary artery disease (CAD) were collected before coronary angiography and analyzed by nuclear magnetic resonance (NMR) spectroscopy. The severity of coronary atherosclerosis was quantified by the Gensini score (≤20.5 = nonsignificant coronary atherosclerosis, 20.6–30.0 = intermediate coronary atherosclerosis, ≥30.1 = significant CAD). Differences in lipoprotein subfractions between the three Gensini groups were assessed by two-way ANOVA, adjusted for statin use. Despite no differences in conventional lipid measures between the three Gensini groups, patients with significant CAD had higher apolipoprotein-B/apolipoprotein-A1 ratio, 30% more small and dense low-density lipoprotein 5 (LDL-5) particles, and increased levels of cholesterol, triglycerides, and phospholipids within LDL-5 compared with patients with nonsignificant coronary atherosclerosis and intermediate coronary atherosclerosis ( P ≤ 0.001). In addition, the low-density lipoprotein (LDL) cholesterol/high-density lipoprotein cholesterol ratio, and triglyceride levels of LDL 4 were significantly increased in patients with significant CAD compared with patients with nonsignificant coronary atherosclerosis. In conclusion, small and dense lipoprotein subfractions were associated with coronary atherosclerosis in patients without prior CVD. Additional studies are needed to explore whether lipoprotein subfractions may represent biomarkers offering a clinically meaningful improvement in the risk prediction of CAD.
38.	Sjogren, RJO, et al. (author) Temporal analysis of reciprocal miRNA-mRNA expression patterns predicts regulatory networks during differentiation in human skeletal muscle cells 2015 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 47:3, s. 45-57 Journal article (peer-reviewed)abstract microRNAs (miRNAs) are short noncoding RNAs that regulate gene expression through posttranscriptional repression of target genes. miRNAs exert a fundamental level of control over many developmental processes, but their role in the differentiation and development of skeletal muscle from myogenic progenitor cells in humans remains incompletely understood. Using primary cultures established from human skeletal muscle satellite cells, we performed microarray profiling of miRNA expression during differentiation of myoblasts ( day 0) into myotubes at 48 h intervals ( day 2, 4, 6, 8, and 10). Based on a time-course analysis, we identified 44 miRNAs with altered expression [false discovery rate (FDR) < 5%, fold change > ±1.2] during differentiation, including the marked upregulation of the canonical myogenic miRNAs miR-1, miR-133a, miR-133b, and miR-206. Microarray profiling of mRNA expression at day 0, 4, and 10 identified 842 and 949 genes differentially expressed (FDR < 10%) at day 4 and 10, respectively. At day 10, 42% of altered transcripts demonstrated reciprocal expression patterns in relation to the directional change of their in silico predicted regulatory miRNAs based on analysis using Ingenuity Pathway Analysis microRNA Target Filter. Bioinformatic analysis predicted networks of regulation during differentiation including myomiRs miR-1/206 and miR-133a/b, miRNAs previously established in differentiation including miR-26 and miR-30, and novel miRNAs regulated during differentiation of human skeletal muscle cells such as miR-138-5p and miR-20a. These reciprocal expression patterns may represent new regulatory nodes in human skeletal muscle cell differentiation. This analysis serves as a reference point for future studies of human skeletal muscle differentiation and development in healthy and disease states.
39.	Synnergren, Jane, et al. (author) Comparative transcriptomic analysis identifies genes differentially expressed in human epicardial progenitors and hiPSC-derived cardiac progenitors 2016 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 48:11, s. 771-784 Journal article (peer-reviewed)abstract Comparative transcriptomic analysis identifies genes differentially expressed in human epicardial progenitor cells and hiPSC-derived cardiac progenitor cells: effects of hypoxic vs normoxic culture conditions.
40.	Synnergren, Jane, 1967, et al. (author) Expression of microRNAs and their target mRNAs in human stem cell-derived cardiomyocyte clusters and in heart tissue. 2011 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 43:10, s. 581-94 Journal article (peer-reviewed)abstract Recent studies have shown that microRNAs (miRNAs) act as posttranscriptional regulators and that they play important roles during heart development and in cardiac function. Thus, they may provide new means of altering stem cell fate and differentiation processes. However, information about the correlation between global miRNA and mRNA expression in cardiomyocyte clusters (CMCs) derived from human embryonic stem cells (hESC) and in fetal and adult heart tissue is lacking. In the present study the global miRNA and mRNA expression in hESC-derived CMCs and in fetal and adult heart tissue was investigated in parallel using microarrays. Target genes for the differentially expressed miRNAs were predicted using computational methods, and the concordance in miRNA expression and mRNA levels of potential target genes was determined across the experimental samples. The biology of the predicted target genes was further explored regarding their molecular functions and involvement in known regulatory pathways. A clear correlation between the global miRNA expression and corresponding target mRNA expression was observed. Using three different sources of cardiac tissue-like samples, we defined the similarities between in vitro hESC-derived CMCs and their in vivo counterparts. The results are in line with previously reported observations that miRNAs repress mRNA expression and additionally identify a number of novel miRNAs with potential important roles in human cardiac tissue. The concordant miRNA expression pattern observed among all the cardiac tissue-like samples analyzed here provide a starting point for future ambitious studies aiming towards assessment of the functional roles of specific miRNAs during cardiomyocyte differentiation.
41.	Synnergren, Jane, et al. (author) Global transcriptional profiling reveals similarities and differences between human stem cell-derived cardiomyocyte clusters and heart tissue 2012 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 44:4, s. 245-258 Journal article (peer-reviewed)abstract It is now well documented that human embryonic stem cells (hESCs) can differentiate into functional cardiomyocytes. These cells constitute a promising source of material for use in drug development, toxicity testing, and regenerative medicine. To assess their utility as replacement or complement to existing models, extensive phenotypic characterization of the cells is required. In the present study, we used microarrays and analyzed the global transcription of hESC-derived cardiomyocyte clusters (CMCs) and determined similarities as well as differences compared with reference samples from fetal and adult heart tissue. In addition, we performed a focused analysis of the expression of cardiac ion channels and genes involved in the Ca2+-handling machinery, which in previous studies have been shown to be immature in stem cell-derived cardiomyocytes. Our results show that hESC-derived CMCs, on a global level, have a highly similar gene expression profile compared with human heart tissue, and their transcriptional phenotype was more similar to fetal than to adult heart. Despite the high similarity to heart tissue, a number of significantly differentially expressed genes were identified, providing some clues toward understanding the molecular difference between in vivo sourced tissue and stem cell derivatives generated in vitro. Interestingly, some of the cardiacrelated ion channels and Ca2+-handling genes showed differential expression between the CMCs and heart tissues. These genes may represent candidates for future genetic engineering to create hESC-derived CMCs that better mimic the phenotype of the cardiomyocytes present in the adult human heart.
42.	Synnergren, Jane, et al. (author) Transcriptional sex and regional differences in paired human atrial and ventricular cardiac biopsies collected in vivo 2020 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 52:2, s. 110-120 Journal article (peer-reviewed)abstract Transcriptional studies of the human heart provide insight into physiological and pathophysiological mechanisms, essential for understanding the fundamental mechanisms of normal cardiac function and how they are altered by disease. To improve the understanding of why men and women may respond differently to the same therapeutic treatment it is crucial to learn more about sex-specific transcriptional differences. In this study the transcriptome of right atrium and left ventricle was compared across sex and regional location. Paired biopsies from five male and five female patients undergoing aortic valve replacement or coronary artery bypass grafting were included. Gene expression analysis identified 620 differentially expressed transcripts in atrial and ventricular tissue in men and 471 differentially expressed transcripts in women. In total 339 of these transcripts overlapped across sex but notably, 281 were unique in the male tissue and 162 in the female tissue, displaying marked sex differences in the transcriptional machinery. The transcriptional activity was significantly higher in atrias than in ventricles as 70% of the differentially expressed genes were upregulated in the atrial tissue. Furthermore, pathway- and functional annotation analyses performed on the differentially expressed genes showed enrichment for a more heterogeneous composition of biological processes in atrial compared with the ventricular tissue, and a dominance of differentially expressed genes associated with infection disease was observed. The results reported here provide increased insights about transcriptional differences between the cardiac atrium and ventricle but also reveal transcriptional differences in the human heart that can be attributed to sex.
43.	Tollet-Egnell, P, et al. (author) Growth hormone-mediated alteration of fuel metabolism in the aged rat as determined from transcript profiles 2004 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 16:2, s. 261-267 Journal article (peer-reviewed)abstract Age-related changes in body composition and serum lipids resemble symptoms of adult-onset growth hormone (GH) deficiency. GH treatment has been shown to normalize these changes in both GH-deficient adult patients and elderly subjects. The aim of this study was to identify GH-responsive genes that might mediate positive effects of GH treatment on fuel metabolism and body composition. cDNA microarrays were used to analyze age- and GH-induced changes in gene expression patterns in male rats. Tissues analyzed were liver, adipose tissue, and skeletal muscle from animals on or off GH treatment. A value of 1.5 was chosen to denote differences (increased or decreased expression) in the level of mRNA expression. In the liver, 7.3% of the expressed genes were affected by age and 6.5% by GH. Similar values for the other tissues were 8.3% and 5.3% (fat), and 7.9% and 9.6% (muscle), respectively. Among the differentially expressed genes, we identified several that encode proteins involved in fuel metabolism. Old rats were shown to have induced expression of genes involved in hepatic glucose oxidation and lipid synthesis, whereas these pathways were reduced in adipose tissue. GH treatment induced the expression of genes for lipid oxidation in liver and for glucose oxidation in skeletal muscle. In adipose tissue, GH reduced the expression of genes involved in lipogenesis even further. Changes in transcript levels were reflected in serum in terms of altered lipid profiles. Serum levels of triglycerides, high-density lipoprotein (HDL) cholesterol, and total cholesterol were higher in the old animals than in the young and normalized by GH treatment.
44.	Uvnäs-Moberg, Kerstin (author) Oxytocin's anti-inflammatory and proimmune functions in COVID-19: a transcriptomic signature-based approach 2020 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 52, s. 401-407 Journal article (peer-reviewed)abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic, infecting over 16 million people worldwide with a significant mortality rate. However, there is no current Food and Drug Administration-approved drug that treats coronavirus disease 2019 (COVID-19). Damage to T lymphocytes along with the cytokine storm are important factors that lead to exacerbation of clinical cases. Here, we are proposing intravenous oxytocin (OXT) as a candidate for adjunctive therapy for COVID-19. OXT has antiinflammatory and proimmune adaptive functions. Using the Library of Integrated Network-Based Cellular Signatures (LINCS), we used the transcriptomic signature for carbetocin, an OXT agonist, and compared it to gene knockdown signatures of inflammatory (such as interleukin IL-1 beta and IL-6) and proimmune markers (including T cell and macrophage cell markers like CD40 and ARG1). We found that carbetocin's transcriptomic signature has a pattern of concordance with inflammation and immune marker knockdown signatures that are consistent with reduction of inflammation and promotion and sustaining of immune response. This suggests that carbetocin may have potent effects in modulating inflammation, attenuating T cell inhibition, and enhancing T cell activation. Our results also suggest that carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19.
45.	Weinsheimer, Shantel, et al. (author) Integration of expression profiles and genetic mapping data to identify candidate genes in intracranial aneurysm. 2007 In: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 32:1, s. 45-57 Journal article (peer-reviewed)abstract Intracranial aneurysm (IA) is a complex genetic disease for which, to date, 10 loci have been identified by linkage. Identification of the risk-conferring genes in the loci has proven difficult, since the regions often contain several hundreds of genes. An approach to prioritize positional candidate genes for further studies is to use gene expression data from diseased and nondiseased tissue. Genes that are not expressed, either in diseased or nondiseased tissue, are ranked as unlikely to contribute to the disease. We demonstrate an approach for integrating expression and genetic mapping data to identify likely pathways involved in the pathogenesis of a disease. We used expression profiles for IAs and nonaneurysmal intracranial arteries (IVs) together with the 10 reported linkage intervals for IA. Expressed genes were analyzed for membership in Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathways. The 10 IA loci harbor 1,858 candidate genes, of which 1,561 (84%) were represented on the microarrays. We identified 810 positional candidate genes for IA that were expressed in IVs or IAs. Pathway information was available for 294 of these genes and involved 32 KEGG biological function pathways represented on at least 2 loci. A likelihood-based score was calculated to rank pathways for involvement in the pathogenesis of IA. Adherens junction, MAPK, and Notch signaling pathways ranked high. Integration of gene expression profiles with genetic mapping data for IA provides an approach to identify candidate genes that are more likely to function in the pathology of IA.
46.	Yadetie, Fekadu, et al. (author) Liver gene expression in rats in response to the peroxisome proliferator-activated 2003 In: Physiol Genomics. - 1531-2267. ; 15:1, s. 9-19 Journal article (peer-reviewed)
47.	Yu, LQ, et al. (author) Uncovering multiple molecular targets for caffeine using a drug target validation strategy combining A 2A receptor knockout mice with microarray profiling 2009 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 37:3, s. 199-210 Journal article (peer-reviewed)abstract Caffeine is the most widely consumed psychoactive substance and has complex pharmacological actions in brain. In this study, we employed a novel drug target validation strategy to uncover the multiple molecular targets of caffeine using combined A2Areceptor (A2AR) knockouts (KO) and microarray profiling. Caffeine (10 mg/kg) elicited a distinct profile of striatal gene expression in WT mice compared with that by A2AR gene deletion or by administering caffeine into A2AR KO mice. Thus, A2ARs are required but not sufficient to elicit the striatal gene expression by caffeine (10 mg/kg). Caffeine (50 mg/kg) induced complex expression patterns with three distinct sets of striatal genes: 1) one subset overlapped with those elicited by genetic deletion of A2ARs; 2) the second subset elicited by caffeine in WT as well as A2AR KO mice; and 3) the third subset elicited by caffeine only in A2AR KO mice. Furthermore, striatal gene sets elicited by the phosphodiesterase (PDE) inhibitor rolipram and the GABAAreceptor antagonist bicucullin, overlapped with the distinct subsets of striatal genes elicited by caffeine (50 mg/kg) administered to A2AR KO mice. Finally, Gene Set Enrichment Analysis reveals that adipocyte differentiation/insulin signaling is highly enriched in the striatal gene sets elicited by both low and high doses of caffeine. The identification of these distinct striatal gene populations and their corresponding multiple molecular targets, including A2AR, non-A2AR (possibly A1Rs and pathways associated with PDE and GABAAR) and their interactions, and the cellular pathways affected by low and high doses of caffeine, provides molecular insights into the acute pharmacological effects of caffeine in the brain.
48.	Zheleznyakova, GY, et al. (author) Epigenetic research in multiple sclerosis: progress, challenges, and opportunities 2017 In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 49:9, s. 447-461 Journal article (peer-reviewed)abstract Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. MS likely results from a complex interplay between predisposing causal gene variants (the strongest influence coming from HLA class II locus) and environmental risk factors such as smoking, infectious mononucleosis, and lack of sun exposure/vitamin D. However, little is known about the mechanisms underlying MS development and progression. Moreover, the clinical heterogeneity and variable response to treatment represent additional challenges to a comprehensive understanding and efficient treatment of disease. Epigenetic processes, such as DNA methylation and histone posttranslational modifications, integrate influences from the genes and the environment to regulate gene expression accordingly. Studying epigenetic modifications, which are stable and reversible, may provide an alternative approach to better understand and manage disease. We here aim to review findings from epigenetic studies in MS and further discuss the challenges and clinical opportunities arising from epigenetic research, many of which apply to other diseases with similar complex etiology. A growing body of evidence supports a role of epigenetic processes in the mechanisms underlying immune pathogenesis and nervous system dysfunction in MS. However, disparities between studies shed light on the need to consider possible confounders and methodological limitations for a better interpretation of the data. Nevertheless, translational use of epigenetics might offer new opportunities in epigenetic-based diagnostics and therapeutic tools for a personalized care of MS patients.

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Author/Editor: Larsson, Lars (5); Hoffman, Eric P (5); Aare, Sudhakar (4); Radell, Peter (4); Chen, Yi-Wen (4); Eriksson, Lars (2); show more...; Larsson, L (2); Ochala, Julien (2); Eriksson, Lars I (2); Göransson, Hanna (2); Ge, Bing (2); Pastinen, Tomi (2); Lindahl, Anders, 195 ... (2); Carén, Helena, 1979 (1); Martinez, A (1); Radell, P (1); Lars, Larsson (1); Akkad, Hazem (1); Chen, YW (1); Hoffman, EP (1); Norman, Holly S (1); Bergström, Göran, 19 ... (1); Jagodic, M (1); Krook, A (1); Zierath, JR (1); Marabita, F (1); Park, Hee-Bok (1); Karlsson, Göran (1); Alafuzoff, Irina (1); Mallmin, Hans (1); Olsson, Björn (1); Lernmark, Åke (1); Pedrosa-Domellöf, Fa ... (1); Lundin, Samuel B, 19 ... (1); Eriksson, Mikael (1); Fredholm, BB (1); Johansson, Maria E, ... (1); Uvnäs-Moberg, Kersti ... (1); Gan, Li-Ming, 1969 (1); Månsson, Robert (1); Sigvardsson, Mikael (1); Ruhrmann, S (1); Ruas, JL (1); Asplund, A. (1); Altmae, S (1); Khatri, B (1); Cervenka, I (1); Hallböök, Finn (1); Jonsdottir, Ingibjör ... (1); NORSTEDT, G (1); show less...

University: Uppsala University (20); Karolinska Institutet (16); University of Skövde (7); University of Gothenburg (6); Lund University (4); Swedish University of Agricultural Sciences (4); show more...; Umeå University (2); Stockholm University (1); Örebro University (1); Linköping University (1); Chalmers University of Technology (1); The Swedish School of Sport and Health Sciences (1); show less...

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