Long-term chromium picolinate supplementation improves colostrum profile of Santa Ines ewe

Biological Trace Element Research - Chromium (Cr) is a micromineral that is involved in the metabolism of carbohydrates, lipids, ammonia, and nucleic acids; thus, its supplementation can influence...     

Transgenic mouse models for ADHD

Attention-deficit hyperactivity disorder (ADHD) is a developmental disorder characterized by symptoms of inattention, impulsivity and hyperactivity that adversely affect many aspects of life. Whereas the etiology of ADHD remains unknown, growing evidence indicates a genetic involvement in the development of this disorder. The brain circuits associated with ADHD are rich in monoamines, which are involved in the mechanism of action of psychostimulants and other medications used to treat this disorder. Dopamine (DA) is believed to play a major role in ADHD but other neurotransmitters are certainly also involved. Genetically modified mice have become an indispensable tool used to analyze the contribution of genetic factors in the pathogenesis of human disorders. Although rodent models cannot fully recapitulate complex human psychiatric disorders such as ADHD, transgenic mice offer an opportunity to directly investigate in vivo the specific roles of novel candidate genes identified in ADHD patients. Several knock-out and transgenic mouse models have been proposed as ADHD models, mostly based on targeting genes involved in DA transmission, including the gene encoding the dopamine transporter (DAT1). These mutant models provided an opportunity to evaluate the contribution of dopamine-related processes to brain pathology, to dissect the neuronal circuitry and molecular mechanisms involved in the antihyperkinetic action of psychostimulants and to evaluate novel treatments for ADHD. New transgenic models mouse models targeting other genes have recently been proposed for ADHD. Here, we discuss the recent advances and pitfalls in modeling ADHD endophenotypes in genetically altered animals.     

1914G variant of BCHE gene associated with enzyme activity,obesity and triglyceride levels

Polymorphisms of butyrylcholinesterase (BChE) have been reported to be associated to weight, BMI variance and hypertriglyceridemia in adults and adolescents. The aim of the present study was to investigate the association of −116A (SNP: G/A; rs1126680) and 1914G (SNP: A/G; rs3495) variants of BCHE gene with anthropometric and biochemical variables associated with obesity in population sample of 115 individuals, from Southern Brazil. Participants were grouped in two categories: obese (BMI ≥ 30) and non-obese (BMI < 30). The 1914G allele showed significantly higher frequency in the obese group, and carriers of 1914G allele showed lower mean BChE activity when compared to 1914A carriers (p = 0.006). Higher means of BMI (p = 0.02) and triglyceride (TG; p = 0.01) were found in 1914G carriers (BMI = 27.57kg/m²; TG = 150.8 mg/dL) when compared to 1914A homozygotes (BMI = 25.55 kg/m²; TG = 107.9 mg/dL). Carriers of the −116A allele showed lower mean BChE activity than usual homozygotes, and the −116A variant was found in cis with 1914G (p < 0.0001; D′ = 1). The region of BCHE gene that contains the 1914G mutation site is target of microRNAs (miRs) and the response of BChE to glucocorticoids is especially influenced by these miRs. Therefore, it is possible that the 1914G allele can be interfering in gluconeogenesis, hyperglycemia, lipolysis and body fat distribution. This lower activity may cause an imbalance in lipid metabolism, which may lead to an increased predisposition to obesity and to a lower ability to maintain metabolic homeostasis.     

Identifying human-rhesus macaque gene orthologs using heterospecific SNP probes

We genotyped a Chinese and an Indian-origin rhesus macaque using the Affymetrix Genome-Wide Human SNP Array 6.0 and cataloged 85,473 uniquely mapping heterospecific SNPs. These SNPs were assigned to rhesus chromosomes according to their probe sequence alignments as displayed in the human and rhesus reference sequences. The conserved gene order (synteny) revealed by heterospecific SNP maps is in concordance with that of the published human and rhesus macaque genomes.Using these SNPs' original human rs numbers, we identified 12,328 genes annotated in humans that are associated with these SNPs, 3674 of which were found in at least one of the two rhesus macaques studied. Due to their density, the heterospecific SNPs allow fine-grained comparisons, including approximate boundaries of intra- and extra-chromosomal rearrangements involving gene orthologs, which can be used to distinguish rhesus macaque chromosomes from human chromosomes.     

New parasites and predators follow the introduction of two fish species to a subarctic lake: implications for food-web structure and functioning

Introduced species can alter the topology of food webs. For instance, an introduction can aid the arrival of free-living consumers using the new species as a resource, while new parasites may also arrive with the introduced species. Food-web responses to species additions can thus be far more complex than anticipated. In a subarctic pelagic food web with free-living and parasitic species, two fish species (arctic charr Salvelinus alpinus and three-spined stickleback Gasterosteus aculeatus) have known histories as deliberate introductions. The effects of these introductions on the food web were explored by comparing the current pelagic web with a heuristic reconstruction of the pre-introduction web. Extinctions caused by these introductions could not be evaluated by this approach. The introduced fish species have become important hubs in the trophic network, interacting with numerous parasites, predators and prey. In particular, five parasite species and four predatory bird species depend on the two introduced species as obligate trophic resources in the pelagic web and could therefore not have been present in the pre-introduction network. The presence of the two introduced fish species and the arrival of their associated parasites and predators increased biodiversity, mean trophic level, linkage density, and nestedness; altering both the network structure and functioning of the pelagic web. Parasites, in particular trophically transmitted species, had a prominent role in the network alterations that followed the introductions.     

The Bile Acid Receptor TGR5 Does Not Interact with β-Arrestins or Traffic to Endosomes but Transmits Sustained Signals from Plasma Membrane Rafts

TGR5 is a G protein-coupled receptor that mediates bile acid (BA) effects on energy balance, inflammation, digestion, and sensation. The mechanisms and spatiotemporal control of TGR5 signaling are poorly understood. We investigated TGR5 signaling and trafficking in transfected HEK293 cells and colonocytes (NCM460) that endogenously express TGR5. BAs (deoxycholic acid (DCA), taurolithocholic acid) and the selective agonists oleanolic acid and 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated cAMP formation but did not induce TGR5 endocytosis or recruitment of β-arrestins, as assessed by confocal microscopy. DCA, taurolithocholic acid, and oleanolic acid did not stimulate TGR5 association with β-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, as determined by bioluminescence resonance energy transfer. 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated a low level of TGR5 interaction with β-arrestin 2 and GRK2. DCA induced cAMP formation at the plasma membrane and cytosol, as determined using exchange factor directly regulated by cAMP (Epac2)-based reporters, but cAMP signals did not desensitize. AG1478, an inhibitor of epidermal growth factor receptor tyrosine kinase, the metalloprotease inhibitor batimastat, and methyl-β-cyclodextrin and filipin, which block lipid raft formation, prevented DCA stimulation of ERK1/2. Bioluminescence resonance energy transfer analysis revealed TGR5 and EGFR interactions that were blocked by disruption of lipid rafts. DCA stimulated TGR5 redistribution to plasma membrane microdomains, as localized by immunogold electron microscopy. Thus, TGR5 does not interact with β-arrestins, desensitize, or traffic to endosomes. TGR5 signals from plasma membrane rafts that facilitate EGFR interaction and transactivation. An understanding of the spatiotemporal control of TGR5 signaling provides insights into the actions of BAs and therapeutic TGR5 agonists/antagonists.     

Hydralazine and Organic Nitrates Restore Impaired Excitation-Contraction Coupling by Reducing Calcium Leak Associated with Nitroso-Redox Imbalance

Although the combined use of hydralazine and isosorbide dinitrate confers important clinical benefits in patients with heart failure, the underlying mechanism of action is still controversial. We used two models of nitroso-redox imbalance, neuronal NO synthase-deficient (NOS1^−/−) mice and spontaneously hypertensive heart failure rats, to test the hypothesis that hydralazine (HYD) alone or in combination with nitroglycerin (NTG) or isosorbide dinitrate restores Ca²⁺ cycling and contractile performance and controls superoxide production in isolated cardiomyocytes. The response to increased pacing frequency was depressed in NOS1^−/− compared with wild type myocytes. Both sarcomere length shortening and intracellular Ca²⁺ transient (Δ[Ca²⁺]_i) responses in NOS1^−/− cardiomyocytes were augmented by HYD in a dose-dependent manner. NTG alone did not affect myocyte shortening but reduced Δ[Ca²⁺]_i across the range of pacing frequencies and increased myofilament Ca²⁺ sensitivity thereby enhancing contractile efficiency. Similar results were seen in failing myocytes from the heart failure rat model. HYD alone or in combination with NTG reduced sarcoplasmic reticulum (SR) leak, improved SR Ca²⁺ reuptake, and restored SR Ca²⁺ content. HYD and NTG at low concentrations (1 μm), scavenged superoxide in isolated cardiomyocytes, whereas in cardiac homogenates, NTG inhibited xanthine oxidoreductase activity and scavenged NADPH oxidase-dependent superoxide more efficiently than HYD. Together, these results revealed that by reducing SR Ca²⁺ leak, HYD improves Ca²⁺ cycling and contractility impaired by nitroso-redox imbalance, and NTG enhanced contractile efficiency, restoring cardiac excitation-contraction coupling.     

Conservation of Protein Structure over Four Billion Years

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Transmissibility of the Monkeypox Virus Clades via Respiratory Transmission: Investigation Using the Prairie Dog-Monkeypox Virus Challenge System

Monkeypox virus (MPXV) is endemic within Africa where it sporadically is reported to cause outbreaks of human disease. In 2003, an outbreak of human MPXV occurred in the US after the importation of infected African rodents. Since the eradication of smallpox (caused by an orthopoxvirus (OPXV) related to MPXV) and cessation of routine smallpox vaccination (with the live OPXV vaccinia), there is an increasing population of people susceptible to OPXV diseases. Previous studies have shown that the prairie dog MPXV model is a functional animal model for the study of systemic human OPXV illness. Studies with this model have demonstrated that infected animals are able to transmit the virus to naive animals through multiple routes of exposure causing subsequent infection, but were not able to prove that infected animals could transmit the virus exclusively via the respiratory route. Herein we used the model system to evaluate the hypothesis that the Congo Basin clade of MPXV is more easily transmitted, via respiratory route, than the West African clade. Using a small number of test animals, we show that transmission of viruses from each of the MPXV clade was minimal via respiratory transmission. However, transmissibility of the Congo Basin clade was slightly greater than West African MXPV clade (16.7% and 0% respectively). Based on these findings, respiratory transmission appears to be less efficient than those of previous studies assessing contact as a mechanism of transmission within the prairie dog MPXV animal model.     

Measuring Information-Transfer Delays

In complex networks such as gene networks, traffic systems or brain circuits it is important to understand how long it takes for the different parts of the network to effectively influence one another. In the brain, for example, axonal delays between brain areas can amount to several tens of milliseconds, adding an intrinsic component to any timing-based processing of information. Inferring neural interaction delays is thus needed to interpret the information transfer revealed by any analysis of directed interactions across brain structures. However, a robust estimation of interaction delays from neural activity faces several challenges if modeling assumptions on interaction mechanisms are wrong or cannot be made. Here, we propose a robust estimator for neuronal interaction delays rooted in an information-theoretic framework, which allows a model-free exploration of interactions. In particular, we extend transfer entropy to account for delayed source-target interactions, while crucially retaining the conditioning on the embedded target state at the immediately previous time step. We prove that this particular extension is indeed guaranteed to identify interaction delays between two coupled systems and is the only relevant option in keeping with Wiener’s principle of causality. We demonstrate the performance of our approach in detecting interaction delays on finite data by numerical simulations of stochastic and deterministic processes, as well as on local field potential recordings. We also show the ability of the extended transfer entropy to detect the presence of multiple delays, as well as feedback loops. While evaluated on neuroscience data, we expect the estimator to be useful in other fields dealing with network dynamics.