Alterations in hepatic miRNA expression during negative energy balance in postpartum dairy cattle

peer-reviewedBackground Negative energy balance (NEB), an altered metabolic state, occurs in early postpartum dairy cattle when energy demands to support lactation exceed energy intake. During NEB the liver undergoes oxidative stress and increased breakdown of fatty acids accompanied by changes in gene expression. It is now known that micro RNAs (miRNA) can have a role in mediating such alterations in gene expression through repression or degradation of target mRNAs. miRNA expression is known to be altered by metabolism and environmental factors and miRNAs are implicated in expression modulation of metabolism related genes. Results miRNA expression was profiled in the liver of moderate yielding dairy cattle under severe NEB (SNEB) and mild NEB (MNEB) using the Affymetrix Gene Chip miRNA_2.0 array with 679 probe sets for Bos-taurus miRNAs. Ten miRNAs were found to be differentially expressed using the ‘samr’ statistical package (delta = 0.6) at a q-value FDR of < 12%. Five miRNAs including miR-17-5p, miR-31, miR-140, miR-1281 and miR-2885 were validated using RT-qPCR, to be up-regulated under SNEB. Liver diseases associated with these miRNAs include non-alcoholic fatty liver (NAFLD) and hepatocellular carcinoma (HCC). miR-140 and miR-17-5p are known to show differential expression under oxidative stress. A total of 32 down-regulated putative target genes were also identified among 418 differentially expressed hepatic genes previously reported for the same animal model. Among these, GPR37 (G protein-coupled receptor 37), HEYL (hairy/enhancer-of-split related with YRPW motif-like), DNJA1, CD14 (Cluster of differentiation 14) and GNS (glucosamine (N-acetyl)-6-sulfatase) are known to be associated with hepatic metabolic disorders. In addition miR-140 and miR-2885 have binding sites on the most down-regulated of these genes, FADS2 (Fatty acid desaturase 2) which encodes an enzyme critical in lipid biosynthesis. Furthermore, HNF3-gamma (Hepatocyte nuclear factor 3-gamma), a hepatic transcription factor (TF) that is involved in IGF-1 expression regulation and maintenance of glucose homeostasis is a putative target of miR-31. Conclusions This study shows that SNEB affects liver miRNA expression and these miRNAs have putative targets in hepatic genes down-regulated under this condition. This study highlights the potential role of miRNAs in transcription regulation of hepatic gene expression during SNEB in dairy cattle. Background Negative energy balance (NEB), an altered metabolic state, occurs in early postpartum dairy cattle when energy demands to support lactation exceed energy intake. During NEB the liver undergoes oxidative stress and increased breakdown of fatty acids accompanied by changes in gene expression. It is now known that micro RNAs (miRNA) can have a role in mediating such alterations in gene expression through repression or degradation of target mRNAs. miRNA expression is known to be altered by metabolism and environmental factors and miRNAs are implicated in expression modulation of metabolism related genes. Results miRNA expression was profiled in the liver of moderate yielding dairy cattle under severe NEB (SNEB) and mild NEB (MNEB) using the Affymetrix Gene Chip miRNA_2.0 array with 679 probe sets for Bos-taurus miRNAs. Ten miRNAs were found to be differentially expressed using the ‘samr’ statistical package (delta = 0.6) at a q-value FDR of < 12%. Five miRNAs including miR-17-5p, miR-31, miR-140, miR-1281 and miR-2885 were validated using RT-qPCR, to be up-regulated under SNEB. Liver diseases associated with these miRNAs include non-alcoholic fatty liver (NAFLD) and hepatocellular carcinoma (HCC). miR-140 and miR-17-5p are known to show differential expression under oxidative stress. A total of 32 down-regulated putative target genes were also identified among 418 differentially expressed hepatic genes previously reported for the same animal model. Among these, GPR37 (G protein-coupled receptor 37), HEYL (hairy/enhancer-of-split related with YRPW motif-like), DNJA1, CD14 (Cluster of differentiation 14) and GNS (glucosamine (N-acetyl)-6-sulfatase) are known to be associated with hepatic metabolic disorders. In addition miR-140 and miR-2885 have binding sites on the most down-regulated of these genes, FADS2 (Fatty acid desaturase 2) which encodes an enzyme critical in lipid biosynthesis. Furthermore, HNF3-gamma (Hepatocyte nuclear factor 3-gamma), a hepatic transcription factor (TF) that is involved in IGF-1 expression regulation and maintenance of glucose homeostasis is a putative target of miR-31. Conclusions This study shows that SNEB affects liver miRNA expression and these miRNAs have putative targets in hepatic genes down-regulated under this condition. This study highlights the potential role of miRNAs in transcription regulation of hepatic gene expression during SNEB in dairy cattle

The miRNAome of the postpartum dairy cow liver in negative energy balance

peer-reviewedBackground: Negative energy balance (NEB) is an altered metabolic state in high yielding cows that occurs during the first few weeks postpartum when energy demands for lactation and maintenance exceed the energy supply from dietary intake. NEB can, in turn, lead to metabolic disorders and to reduced fertility. Alterations in the expression of more than 700 hepatic genes have previously been reported in a study of NEB in postpartum dairy cows. miRNAs (microRNA) are known to mediate many alterations in gene expression post transcriptionally. To study the hepatic miRNA content of postpartum dairy cows, including their overall abundance and differential expression, in mild NEB (MNEB) and severe NEB (SNEB), short read RNA sequencing was carried out. To identify putative targets of differentially expressed miRNAs among differentially expressed hepatic genes reported previously in dairy cows in SNEB computational target identification was employed. Results: Our results indicate that the dairy cow liver expresses 53 miRNAs at a lower threshold of 10 reads per million. Of these, 10 miRNAs accounted for greater than 95% of the miRNAome (miRNA content). Of the highly expressed miRNAs, miR-122 constitutes 75% followed by miR-192 and miR-3596. Five out of thirteen let-7 miRNA family members are also among the highly expressed miRNAs. miR-143, down-regulated in SNEB, was found to have 4 putative up-regulated gene targets associated with SNEB including LRP2 (low density lipoprotein receptor-related protein 2), involved in lipid metabolism and up-regulated in SNEB. Conclusions: This is the first liver miRNA-seq profiling study of moderate yielding dairy cows in the early postpartum period. Tissue specific miR-122 and liver enriched miR-192 are two of the most abundant miRNAs in the postpartum dairy cow liver. miR-143 is significantly down-regulated in SNEB and putative targets of miRNA-143 which are up-regulated in SNEB, include a gene involved in lipid metabolism.Teagasc Walsh Fellowship Programm

An Investigation of the Effects of Categorization and Discrimination Training on Auditory Perceptual Space

Psychophysical phenomena such as categorical perception and the perceptual magnet effect indicate that our auditory perceptual spaces are warped for some stimuli. This paper investigates the effects of two different kinds of training on auditory perceptual space. It is first shown that categorization training, in which subjects learn to identify stimuli within a particular frequency range as members of the same category, can lead to a decrease in sensitivity to stimuli in that category. This phenomenon is an example of acquired similarity and apparently has not been previously demonstrated for a category-relevant dimension. Discrimination training with the same set of stimuli was shown to have the opposite effect: subjects became more sensitive to differences in the stimuli presented during training. Further experiments investigated some of the conditions that are necessary to generate the acquired similarity found in the first experiment. The results of these experiments are used to evaluate two neural network models of the perceptual magnet effect. These models, in combination with our experimental results, are used to generate an experimentally testable hypothesis concerning changes in the brain's auditory maps under different training conditions.Alfred P. Sloan Foundation and the National institutes of Deafness and other Communication Disorders (R29 02852); Air Force Office of Scientific Research (F49620-98-1-0108

Repurposing designed mutants: a valuable strategy for computer-aided laccase engineering – the case of POXA1b

The broad specificity of laccases, a direct consequence of their shallow binding site, makes this class of enzymes a suitable template to build specificity toward putative substrates. In this work, a computational methodology that accumulates beneficial interactions between the enzyme and the substrate in productive conformations is applied to oxidize 2,4-diamino-benzenesulfonic acid with POXA1b laccase. Although the experimental validation of two designed variants yielded negative results, most likely due to the hard oxidizability of the target substrate, molecular simulations suggest that a novel polar binding scaffold was designed to anchor negatively charged groups. Consequently, the oxidation of three such molecules, selected as representative of different classes of substances with different industrial applications, significantly improved. According to molecular simulations, the reason behind such an improvement lies in the more productive enzyme–substrate binding achieved thanks to the designed polar scaffold. In the future, mutant repurposing toward other substrates could be first carried out computationally, as done here, testing molecules that share some similarity with the initial target. In this way, repurposing would not be a mere safety net (as it is in the laboratory and as it was here) but rather a powerful approach to transform laccases into more efficient multitasking enzymes.This work was funded by INDOX (KBBE-2013-7-613549) European project and CTQ2013-48287-R Spanish National Project. V. G. and E. M. acknowledge Università degli Studi di Napoli and Generalitat de Catalunya for their respective predoctoral fellowships.Peer ReviewedPostprint (author's final draft

Diatoms as a paleoproductivity proxy in the NW Iberian coastal upwelling system (NE Atlantic)

The objective of the current work is to improve our understanding of how water column diatom's abundance and assemblage composition is seasonally transferred from the photic zone to seafloor sediments. To address this, we used a dataset derived from water column, sediment trap and surface sediment samples recovered in the NW Iberian coastal upwelling system. Diatom fluxes (2.2 (+/- 5.6) 10(6) valves m(-2) d(-1)) represented the majority of the siliceous microorganisms sinking out from the photic zone during all studied years and showed seasonal variability. Contrasting results between water column and sediment trap diatom abundances were found during downwelling periods, as shown by the unexpectedly high diatom export signals when diatom- derived primary production achieved their minimum levels. They were principally related to surface sediment remobilization and intense Minho and Douro river discharge that constitute an additional source of particulate matter to the inner continental shelf. In fact, contributions of allochthonous particles to the sinking material were confirmed by the significant increase of both benthic and freshwater diatoms in the sediment trap assemblage. In contrast, we found that most of the living diatom species blooming during highly productive upwelling periods were dissolved during sinking, and only those resistant to dissolution and the Chaetoceros and Leptocylindrus spp. resting spores were susceptible to being exported and buried. Fur-thermore, Chaetoceros spp. dominate during spring-early summer, when persistent northerly winds lead to the upwelling of nutrient-rich waters on the shelf, while Leptocylindrus spp. appear associated with late-summer upwelling relaxation, characterized by water column stratification and nutrient depletion. These findings evidence that the contributions of these diatom genera to the sediment's total marine diatom assemblage should allow for the reconstruction of different past upwelling regimes.CAIBEX [CTM2007-66408-C02-01/MAR]; REIMAGE [CTM2011-30155-C03-03]; Spanish Government, EXCAPA project [10MDS402013PR]; Xunta de Galicia; EU FEDER [INTERREG 2009/2011-0313/RAIA/E]; RAIA. co [INTERREG2011/2013-052/RAIA.co/1E]; CALIBERIA project [PTDC/MAR/102045/2008]; Fundacao para a Ciencia e a Tecnologia (FCT-Portugal) [COMPETE/FEDER-FCOMP01-0124-FEDER-010599]; Xunta de Galicia (Spain) [SFRH/BPD/111433/2015]; FCT (Portugal) [SFRH/BPD/111433/2015]; [SFRH/BD/88439/2012

County-Level Hispanic Ethnic Density and Cardiovascular Disease Mortality.

Background Hispanics are the fastest growing ethnic group in the United States, and little is known about how Hispanic ethnic population density impacts cardiovascular disease ( CVD ) mortality. Methods and Results We examined county-level deaths for Hispanics and non-Hispanic whites from 2003 to 2012 using data from the National Center for Health Statistics' Multiple Cause of Death mortality files. Counties with more than 20 Hispanic deaths (n=715) were included in the analyses. CVD deaths were identified using International Classification of Diseases, Tenth Revision (ICD-10), I00 to I78, and population estimates were calculated using linear interpolation from 2000 and 2010 census data. Multivariate linear regression was used to examine the association of Hispanic ethnic density with Hispanic and non-Hispanic white age-adjusted CVD mortality rates. County-level age-adjusted CVD mortality rates were adjusted for county-level demographic, socioeconomic, and healthcare factors. There were a total of 4 769 040 deaths among Hispanics (n=382 416) and non-Hispanic whites (n=4 386 624). Overall, cardiovascular age-adjusted mortality rates were higher among non-Hispanic whites compared with Hispanics (244.8 versus 189.0 per 100 000). Hispanic density ranged from 1% to 96% in each county. Counties in the highest compared with lowest category of Hispanic density had 60% higher Hispanic mortality (215.3 versus 134.2 per 100 000 population). In linear regression models, after adjusting for county-level demographic, socioeconomic, and healthcare factors, increasing Hispanic ethnic density remained strongly associated with mortality for Hispanics but not for non-Hispanic whites. Conclusions CVD mortality is higher in counties with higher Hispanic ethnic density. County-level characteristics do not fully explain the higher CVD mortality among Hispanics in ethnically concentrated counties

Total Quality Management, Entrepreneurial Orientation and Small Enterprises' Performance in Abuja, Nigeria- A Research

The influences and combined effects of Total Quality Management (TQM), Entrepreneurial Orientation (EO) on small entreprise’s performance is the main concern of this paper as has been evident in the literature. Though, research findings on the relationship between these variables (TQM and EO) were reported in isolation. Yet, the finding is often described as contradictory and inconclusive. Therefore, this study investigated the combined effect of total quality management and entrepreneurial orientation on SMEs performance in Abuja, Nigeria. Data was collected from 171 owners/managers of small entreprises and analyzed using SPSS and PLS-SEM statistical tool of analysis. Findings revealed that has significant positive effect on small enterprise’s performance. On the other hand, EO has significant negative effect on small enterprise’s performance. Research implications were provided to small enterprises’ owners/managers on the need to adopt TQM practices to strengthen the effect of EO on performance of small enterprises. Future researchers can examine the model using different sample sizes or apply the model in an entirely new research context

Dislocation Dynamics in an Anisotropic Stripe Pattern

The dynamics of dislocations confined to grain boundaries in a striped system are studied using electroconvection in the nematic liquid crystal N4. In electroconvection, a striped pattern of convection rolls forms for sufficiently high driving voltages. We consider the case of a rapid change in the voltage that takes the system from a uniform state to a state consisting of striped domains with two different wavevectors. The domains are separated by domain walls along one axis and a grain boundary of dislocations in the perpendicular direction. The pattern evolves through dislocation motion parallel to the domain walls. We report on features of the dislocation dynamics. The kinetics of the domain motion are quantified using three measures: dislocation density, average domain wall length, and the total domain wall length per area. All three quantities exhibit behavior consistent with power law evolution in time, with the defect density decaying as $t^{-1/3}$, the average domain wall length growing as $t^{1/3}$, and the total domain wall length decaying as $t^{-1/5}$. The two different exponents are indicative of the anisotropic growth of domains in the system.Comment: 8 figures: 7 jpeg and 1 pd

Integrative AI-Driven Strategies for Advancing Precision Medicine in Infectious Diseases and Beyond: A Novel Multidisciplinary Approach

Precision medicine, tailored to individual patients based on their genetics, environment, and lifestyle, shows promise in managing complex diseases like infections. Integrating artificial intelligence (AI) into precision medicine can revolutionize disease management. This paper introduces a novel approach using AI to advance precision medicine in infectious diseases and beyond. It integrates diverse fields, analyzing patients' profiles using genomics, proteomics, microbiomics, and clinical data. AI algorithms process vast data, providing insights for precise diagnosis, treatment, and prognosis. AI-driven predictive modeling empowers healthcare providers to make personalized and effective interventions. Collaboration among experts from different domains refines AI models and ensures ethical and robust applications. Beyond infections, this AI-driven approach can benefit other complex diseases. Precision medicine powered by AI has the potential to transform healthcare into a proactive, patient-centric model. Research is needed to address privacy, regulations, and AI integration into clinical workflows. Collaboration among researchers, healthcare institutions, and policymakers is crucial in harnessing AI-driven strategies for advancing precision medicine and improving patient outcomes