•The study focuses on bull fertility including conception rate and semen traits.•The genetic parameters for bull fertility were estimated in Japanese Black bulls.•Heritability of the bull conception ...rate was low.•The genetic correlation between bull conception rate and semen motility was high.•Genetic selection for sperm motility could lead to improve bull conception rate.
The P of achieving pregnancy is an important trait of bull fertility in beef cattle and is defined as the bull conception rate (BCR). This study aimed to clarify and better understand the genetic architecture of the BCR calculated using artificial insemination and pregnancy diagnosis records from a progeny testing program in Japanese Black bulls. In this study, we estimated the genetic parameters of the BCR and their correlation with semen production traits. In addition, we assessed the correlated responses in BCR by considering the selection of semen production traits. Nine hundred and sixteen Japanese Black bulls were selected based on fertility, with 28 869 pregnancy diagnostic records from the progeny testing program. Our results showed that the heritability estimate was 0.04 in the BCR at the first service and 0.14 in BCR for the three services, and an increase in the inbreeding coefficient led to a significant decrease in BCR. The phenotypic trend of BCR remained almost constant over the years, whereas the genetic trend increased. In addition, the changes in the progeny testing year effect showed a similar tendency to the phenotypic trends, suggesting that the phenotypic trends could be mainly due to non-genetic effects, including progeny testing year effects. The estimated genetic correlation of BCR with sperm motility traits was favorably moderate to high (ranging from 0.49 to 0.97), and those with sperm quantity traits such as semen volume were favorably low to moderate (ranging from 0.23 to 0.51). In addition, the correlated responses in BCR at the first service by selection for sperm motility traits resulted in a higher genetic gain than direct selection. This study provides new insights into the genetic factors affecting BCR and the possibility of implementing genetic selection to improve BCR by selecting sperm motility traits in Japanese Black bulls.
•Non-additive genetic effect could impact on semen production traits.•Genome-wide association studies were performed in beef and dairy bulls.•The significant non-additive quantitative trait loci were ...detected in each breed.•The highest non-additive effect on chromosome 17 was detected in dairy bulls.•Effective genetic selection can be achieved by removing risk alleles.
Semen production traits are important aspects of bull fertility, because semen quantity leads to direct profits for artificial insemination centres, and semen quality is associated with the probability of achieving a pregnancy. Most genome-wide association studies (GWASs) for semen production traits have assumed that each quantitative trait locus (QTL) has an additive effect. However, GWASs that account for non-additive effects are also important in fitness traits, such as bull fertility. Here, we performed a GWAS using models that accounted for additive and non-additive effects to evaluate the importance of non-additive effects on five semen production traits in beef and dairy bulls. A total of 65 463 records for 615 Japanese Black bulls (JB) and 50 734 records for 873 Holstein bulls (HOL), which were previously genotyped using the Illumina BovineSNP50 BeadChip, were used to estimate genetic parameters and perform GWAS. The heritability estimates were low (ranged from 0.11 to 0.23), and the repeatability estimates were low to moderate (ranged from 0.28 to 0.45) in both breeds. The estimated repeatability was approximately twice as high as the estimated heritability for all traits. In this study, only one significant region with an additive effect was detected in each breed, but multiple significant regions with non-additive effects were detected for each breed. In particular, the region at approximately 64 Mbp on Bos taurus autosome 17 had the highest significant non-additive effect on four semen production traits in HOL. The rs41843851 single nucleotide polymorphism (SNP) in the region had a much lower P-value for the non-additive effect (P-value = 1.1 × 10−31) than for the additive effect (P-value = 1.1 × 10−8) in sperm motility. The AA and AB genotypes on the SNP had a higher phenotype than the BB genotype in HOL, and there was no bull with the BB genotype in JB. Our results showed that non-additive QTLs affect semen production traits, and a novel QTL accounting for non-additive effects could be detected by GWAS. This study provides new insights into non-additive QTLs that affect fitness traits, such as semen production traits in beef and dairy bulls.
Aims/hypothesis
The impact of AGEs and advanced lipoxidation end-products (ALEs) on neuronal and Müller glial dysfunction in the diabetic retina is not well understood. We therefore sought to ...identify dysfunction of the retinal Müller glia during diabetes and to determine whether inhibition of AGEs/ALEs can prevent it.
Methods
Sprague–Dawley rats were divided into three groups: (1) non-diabetic; (2) untreated streptozotocin-induced diabetic; and (3) diabetic treated with the AGE/ALE inhibitor pyridoxamine for the duration of diabetes. Rats were killed and their retinas were evaluated for neuroglial pathology.
Results
AGEs and ALEs accumulated at higher levels in diabetic retinas than in controls (
p
< 0.001). AGE/ALE immunoreactivity was significantly diminished by pyridoxamine treatment of diabetic rats. Diabetes was also associated with the up-regulation of the oxidative stress marker haemoxygenase-1 and the induction of glial fibrillary acidic protein production in Müller glia (
p
< 0.001). Pyridoxamine treatment of diabetic rats had a significant beneficial effect on both variables (
p
< 0.001). Diabetes also significantly altered the normal localisation of the potassium inwardly rectifying channel Kir4.1 and the water channel aquaporin 4 to the Müller glia end-feet interacting with retinal capillaries. These abnormalities were prevented by pyridoxamine treatment.
Conclusions/interpretation
While it is established that AGE/ALE formation in the retina during diabetes is linked to microvascular dysfunction, this study suggests that these pathogenic adducts also play a role in Müller glial dysfunction.
Summary
Background
Lymphoedema is a debilitating progressive condition that is frequently observed following cancer surgery and severely restricts quality of life. Although it is known that lymphatic ...dysfunction and obstruction underlie lymphoedema, the pathogenic mechanism is poorly understood. Smooth muscle cells (SMCs) play pivotal roles in the pathogenesis of various vascular diseases, including atherosclerosis.
Objectives
We analysed SMCs in lymphatic vessels from the lymphoedematous legs of 29 patients.
Methods
Expression of smooth muscle α‐actin (SMαA) and smooth muscle myosin heavy chain (SM‐MHC) isoforms SM1 and SM2 was investigated using immunohistochemistry.
Results
Compared with normal lymphatic vessels, all affected lymphatic vessels in chronic lymphoedema showed marked wall thickening. In addition to increases in the numbers of rows of SMαA+ SM1+ SMCs in the tunica media, SMCs were also observed in the subendothelial region (tunica intima). While most intimal and medial cells were positive for SMαA and SM1, staining for SM1 and particularly SM2, a marker of mature SMCs, progressively declined in lymphatic vessels in increasingly severe lymphoedema lesions. Consequently, the SM1+ and SM2+ cell fractions were significantly reduced in the tunica media and intima of lymphatic vessels.
Conclusions
These observations indicate that the lymphatic tunica media and tunica intima consist mainly of phenotypically modulated SMCs, and that SMCs play a key role in the development of lymphoedema.
What's already known about this topic?
Lymphoedema is a debilitating progressive condition that is frequently observed following cancer surgery and severely restricts quality of life.
Although it is known that lymphatic dysfunction and obstruction underlie lymphoedema, the pathogenic mechanism is poorly understood.
What does this study add?
Lymphatic smooth muscle cells play a key role in the development of lymphoedema.
Abstract
In recent years, we have been witnessing a paradigm shift in computational materials science. In fact, traditional methods, mostly developed in the second half of the XXth century, are being ...complemented, extended, and sometimes even completely replaced by faster, simpler, and often more accurate approaches. The new approaches, that we collectively label by machine learning, have their origins in the fields of informatics and artificial intelligence, but are making rapid inroads in all other branches of science. With this in mind, this Roadmap article, consisting of multiple contributions from experts across the field, discusses the use of machine learning in materials science, and share perspectives on current and future challenges in problems as diverse as the prediction of materials properties, the construction of force-fields, the development of exchange correlation functionals for density-functional theory, the solution of the many-body problem, and more. In spite of the already numerous and exciting success stories, we are just at the beginning of a long path that will reshape materials science for the many challenges of the XXIth century.
Adiponectin (Ad) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. However, the signaling pathways that mediate the metabolic effects of Ad ...remain poorly identified. Here we show that phosphorylation and activation of the 5'-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full-length Ad in the liver. In parallel with its activation of AMPK, Ad stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK. Our data may provide a novel paradigm that an adipocyte-derived antidiabetic hormone, Ad, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Adiponectin is an adipocyte-derived hormone, which has been shown to play important roles in the regulation of glucose and lipid metabolism. Eight mutations in human adiponectin have been reported, ...some of which were significantly related to diabetes and hypoadiponectinemia, but the molecular mechanisms of decreased plasma levels and impaired action of adiponectin mutants were not clarified. Adiponectin structurally belongs to the complement 1q family and is known to form a characteristic homomultimer. Herein, we demonstrated that simple SDS-PAGE under non-reducing and non-heat-denaturing conditions clearly separates multimer species of adiponectin. Adiponectin in human or mouse serum and adiponectin expressed in NIH-3T3 or Escherichia coli formed a wide range of multimers from trimers to high molecular weight (HMW) multimers. A disulfide bond through an amino-terminal cysteine was required for the formation of multimers larger than a trimer. An amino-terminal Cys-Ser mutation, which could not form multimers larger than a trimer, abrogated the effect of adiponectin on the AMP-activated protein kinase pathway in hepatocytes. Among human adiponectin mutations, G84R and G90S mutants, which are associated with diabetes and hypoadiponectinemia, did not form HMW multimers. R112C and I164T mutants, which are associated with hypoadiponectinemia, did not assemble into trimers, resulting in impaired secretion from the cell. These data suggested impaired multimerization and/or the consequent impaired secretion to be among the causes of a diabetic phenotype or hypoadiponectinemia in subjects having these mutations. In conclusion, not only total concentrations, but also multimer distribution should always be considered in the interpretation of plasma adiponectin levels in health as well as various disease states.
Recently, several groups have carried out whole-genome association studies in European and European-origin populations and found novel type 2 diabetes-susceptibility genes, fat mass and obesity ...associated (FTO), solute carrier family 30 (zinc transporter), member 8 (SLC30A8), haematopoietically expressed homeobox (HHEX), exostoses (multiple) 2 (EXT2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which had not been in the list of functional candidates. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) in these genes and type 2 diabetes in participants from the Japanese population.
Sixteen previously reported SNPs were genotyped in 864 Japanese type 2 diabetes individuals (535 men and 329 women; age 63.1 +/- 9.5 years (mean+/-SD), BMI 24.3 +/- 3.9 kg/m(2)) and 864 Japanese control individuals (386 men and 478 women; age 69.5 +/- 6.8 years, BMI 23.8 +/- 3.7 kg/m(2)).
The SNPs rs5015480 odds ratio (OR) = 1.46 (95% CI 1.20-1.77), p = 2.0 x 10(-4), rs7923837 OR = 1.40 (95% CI 1.17-1.68), p = 2.0 x 10(-4) and rs1111875 OR = 1.30 (95% CI 1.11-1.52), p = 0.0013 in HHEX were significantly associated with type 2 diabetes with the same direction as previously reported. SNP rs8050136 in FTO was nominally associated with type 2 diabetes OR = 1.22 (95% CI 1.03-1.46), p = 0.025. SNPs in other genes such as rs7756992 in CDKAL1, rs10811661 in CDKN2B and rs13266634 in SLC30A8 showed nominal association with type 2 diabetes. rs7756992 in CDKAL1 and rs10811661 in CDKN2B were correlated with impaired pancreatic beta cell function as estimated by the homeostasis model assessment beta index (p = 0.023, p = 0.0083, respectively).
HHEX is a common type 2 diabetes-susceptibility gene across different ethnic groups.
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