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Supplementing trace minerals is common in managing bovine respiratory disease (BRD) in post-weaned cattle; however, its influence on host immunity and metabolism in high-risk cattle remains unclear. We aimed to assess the impact of three supplementation programs on liver and serum trace element concentrations and blood gene expression. Fifty-six high-risk beef steers were randomly assigned to one of three groups over 60 days: (1) sulfate-sourced Cu, Co, Mn, and Zn (INR), (2) amino acid-complexed Cu, Mn, Co, and Zn (AAC), or (3) AAC plus trace mineral and vitamin drench (COMBO). Serum and liver biopsies for Cu, Co, Mn, and Zn at d0, d28, and d60 were analyzed from cattle free of BRD (n = 9 INR; n = 6 AAC; n = 10 COMBO). Differences and correlations of mineral concentrations were analyzed via generalized linear mixed models and Spearman's rank coefficients, respectively (p < 0.05). Whole blood RNA samples from healthy cattle (n = 4 INR; n = 4 AAC; n = 4 COMBO) at d0, d13, d28, d45, and d60 were sequenced and analyzed for differentially expressed genes (DEGs) via glmmSeq (FDR < 0.05), edgeR (FDR < 0.10), and Trendy (p < 0.10). Serum and liver Cu and Co concentrations increased over time in all groups, with higher liver Cu in COMBO (487.985 µg/g) versus AAC (392.043 µg/g) at d60 (p = 0.013). Serum and liver Cu concentrations (ρ = 0.579, p = 6.59 × 10-8) and serum and liver Co concentrations (ρ = 0.466, p = 2.80 × 10-5) were linearly correlated. Minimal gene expression differences were found between AAC versus COMBO (n = 2 DEGs) and INR versus COMBO (n = 0 DEGs) over time. AAC versus INR revealed 107 DEGs (d13-d60) with increased traits in AAC including metabolism of carbohydrates/fat-soluble vitamins, antigen presentation, ATPase activity, and B- and T-cell activation, while osteoclast differentiation and neutrophil degranulation decreased in AAC compared to INR. Our study identifies gene expression differences in high-risk cattle fed inorganic or amino acid-complexed mineral supplements, revealing adaptive immune and metabolic mechanisms that may be improved by organically sourced supplementation.
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To investigate effects of inorganic or complexed trace mineral source (zinc, copper, manganese, and cobalt) on receiving period performance and morbidity, crossbred beef heifer calves (nâ =â 287) arriving on three delivery dates were used in a 42-d receiving trial. Heifers were processed after arrival, stratified by day -1 body weights (BW) and allocated randomly to eight pens (11 to 13 heifers/pen, 24 pens total). Within truckload, pens were assigned randomly to dietary treatment (nâ =â 12 pens/treatment). Heifers were housed on 0.42-ha grass paddocks, provided ad libitum bermudagrass hay and provided dietary treatments in grain supplements fed daily. Treatments consisted of supplemental zinc (360 mg/d), copper (125 mg/d), manganese (200 mg/d), and cobalt (12 mg/d) from complexed (Zinpro Availa 4, Zinpro Corp. Eden Prairie, MN) or inorganic sources (sulfates). Heifers were observed daily for clinical bovine respiratory disease (BRD). If presenting BRD symptoms and rectal temperatureâ ≥â 40 °C, heifers were deemed morbid and treated with antibiotics. Six heifers/pen were bled to determine serum haptoglobin concentrations on days 0, 14, and 28. Liver biopsies were taken on day 5â ±â 2 and 43â ±â 1 from three calves selected randomly from each pen for mineral status comparisons. Statistical analyses were performed using the MIXED, GLIMMIX, and repeated measures procedures of SAS 9.4 with truckload as a random effect and pen within truckload specified as subject. There tended to be a treatment by day interaction for BW (Pâ =â 0.07). Heifer BW did not differ on day 0 (Pâ =â 0.82) and day 14 (Pâ =â 0.36), but heifers fed complexed trace minerals had greater BW on day 28 (Pâ =â 0.04) and day 42 (Pâ =â 0.05). Overall average daily gains were greater for heifers fed complexed trace minerals (Pâ =â 0.05; 0.78 vs. 0.70 kg, SEâ =â 0.03). Heifers supplemented with inorganic trace minerals had greater BRD incidence (Pâ =â 0.03; 58 vs. 46%, SEâ =â 3.6). Haptoglobin concentrations decreased throughout the trial (Pâ <â 0.001), and heifers fed complexed trace minerals tended to have a decrease in haptoglobin concentrations (Pâ =â 0.07). The source of trace mineral supplementation had no effect (Pâ ≥â 0.20) on liver mineral concentrations and there were no treatmentâ ×â day interactions (Pâ ≥â 0.35). In conclusion, supplementing diets for the first 42 d after arrival with complexed trace mineral sources improved heifer performance as compared to heifers supplemented with inorganic trace minerals.
Issues associated with health and management of newly received cattle continue to pose significant animal welfare and economic challenges for the beef industry. Diagnosis of bovine respiratory disease, accompanied with poor growth performance, can be addressed by nutritional intervention in receiving cattle. Trace mineral inclusion in receiving rations is vital to calf performance. There are numerous sources of trace mineral supplements that exist commercially for cattle and their effects on immune function, growth, and performance measures were evaluated. Organic trace mineral supplements are being used in replacement of inorganic salts due to potentially greater bioavailability and functionality. An organic source that is commonly used are amino acid complexes. Replacing inorganic sources with complexed sources of trace minerals (zinc, copper, manganese, and cobalt) improved growth performance and decreased sickness during the 42-d receiving study.
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Oligoelementos , Bovinos , Animais , Feminino , Oligoelementos/farmacologia , Manganês/farmacologia , Cobre/farmacologia , Haptoglobinas/análise , Suplementos Nutricionais , Minerais/farmacologia , Zinco/farmacologia , Cobalto/farmacologia , Dieta/veterinária , Peso Corporal , Ração Animal/análiseRESUMO
Acetylcholine (ACh) in cortical neural circuits mediates how selective attention is sustained in the presence of distractors and how flexible cognition adjusts to changing task demands. The cognitive domains of attention and cognitive flexibility might be differentially supported by the M1 muscarinic acetylcholine receptor (mAChR) subtype. Understanding how M1 mAChR mechanisms support these cognitive subdomains is of highest importance for advancing novel drug treatments for conditions with altered attention and reduced cognitive control including Alzheimer's disease or schizophrenia. Here, we tested this question by assessing how the subtype-selective M1 mAChR positive allosteric modulator (PAM) VU0453595 affects visual search and flexible reward learning in nonhuman primates. We found that allosteric potentiation of M1 mAChRs enhanced flexible learning performance by improving extradimensional set shifting, reducing latent inhibition from previously experienced distractors and reducing response perseveration in the absence of adverse side effects. These procognitive effects occurred in the absence of apparent changes of attentional performance during visual search. In contrast, nonselective ACh modulation using the acetylcholinesterase inhibitor (AChEI) donepezil improved attention during visual search at doses that did not alter cognitive flexibility and that already triggered gastrointestinal cholinergic side effects. These findings illustrate that M1 mAChR positive allosteric modulation enhances cognitive flexibility without affecting attentional filtering of distraction, consistent with M1 activity boosting the effective salience of relevant over irrelevant objects specifically during learning. These results suggest that M1 PAMs are versatile compounds for enhancing cognitive flexibility in disorders spanning schizophrenia and Alzheimer's diseases.
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Acetilcolinesterase , Doença de Alzheimer , Animais , Regulação Alostérica/fisiologia , Colinérgicos/farmacologia , Acetilcolina/farmacologia , Cognição , Doença de Alzheimer/tratamento farmacológico , Primatas , Receptor Muscarínico M1RESUMO
The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes.
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Microbioma Gastrointestinal , Verrucomicrobia , Camundongos , Animais , Verrucomicrobia/genética , Microbioma Gastrointestinal/genética , Akkermansia/genética , FenótipoRESUMO
Degeneration of the cholinergic basal forebrain is implicated in the development of cognitive deficits and sleep/wake architecture disturbances in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Indirect-acting muscarinic cholinergic receptor agonists, such as acetylcholinesterase inhibitors (AChEIs), remain the only FDA-approved treatments for the cognitive impairments observed in AD that target the cholinergic system. Novel direct-acting muscarinic cholinergic receptor agonists also improve cognitive performance in young and aged preclinical species and are currently under clinical development for AD. However, little is known about the effects of direct-acting muscarinic cholinergic receptor agonists on disruptions of sleep/wake architecture and arousal observed in nonpathologically aged rodents, nonhuman primates, and clinical populations. The purpose of the present study was to provide the first assessment of the effects of the direct-acting M1/M4-preferring muscarinic cholinergic receptor agonist xanomeline on sleep/wake architecture and arousal in young and nonpathologically aged mice, in comparison with the AChEI donepezil, when dosed in either the active or inactive phase of the circadian cycle. Xanomeline produced a robust reversal of both wake fragmentation and disruptions in arousal when dosed in the active phase of nonpathologically aged mice. In contrast, donepezil had no effect on either age-related wake fragmentation or arousal deficits when dosed during the active phase. When dosed in the inactive phase, both xanomeline and donepezil produced increases in wake and arousal and decreases in nonrapid eye movement sleep quality and quantity in nonpathologically aged mice. Collectively, these novel findings suggest that direct-acting muscarinic cholinergic agonists such as xanomeline may provide enhanced wakefulness and arousal in nonpathological aging, MCI, and AD patient populations.
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Nível de Alerta , Agonistas Muscarínicos , Transtornos Neurocognitivos , Receptor Muscarínico M1 , Receptor Muscarínico M4 , Sono , Animais , Camundongos , Acetilcolinesterase/metabolismo , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Colinérgicos/farmacologia , Colinérgicos/uso terapêutico , Donepezila/farmacologia , Donepezila/uso terapêutico , Agonistas Muscarínicos/farmacologia , Agonistas Muscarínicos/uso terapêutico , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M4/agonistas , Receptor Muscarínico M4/metabolismo , Tiadiazóis/farmacologia , Tiadiazóis/uso terapêutico , Vigília/efeitos dos fármacos , Vigília/fisiologia , Sono/efeitos dos fármacos , Sono/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Transtornos Neurocognitivos/tratamento farmacológico , Transtornos Neurocognitivos/metabolismoRESUMO
Trace minerals are known to play important roles in early embryo development. The study objective was to determine effects of trace mineral source on heifer reproductive performance. Beef heifers (n = 129) were randomly assigned to one of two treatments. From weaning through breeding, all heifers were individually fed a basal diet supplemented with cobalt (Co), copper (Cu), manganese (Mn), and zinc (Zn) either from organic sources (COMP; Cu, Mn, and Zn amino acid complexes and Co glucoheptonate; Availa-4, Zinpro Corporation, Eden Prairie, MN) or inorganic sources (INORG; Cu, Mn, and Zn hydroxychlorides; Intellibond C, M, and Z, Micronutrients, Indianapolis, IN) and Co as CoSO4. Blood samples and a reproductive tract score (RTS) were collected to determine pubertal status. All animals were synchronized and artificially inseminated. Pregnancy status was determined by lymphocyte gene expression, circulating concentrations of pregnancy-associated glycoproteins (PAGs), and by transrectal ultrasonography after artificial insemination. Embryonic loss was defined as when a previously pregnant animal was subsequently diagnosed not pregnant. Data were analyzed using the MIXED procedure in SAS. Puberty (P = 0.44), pelvic area (P = 0.74), RTS (P = 0.49), and estrus expression (P = 0.82) were not influenced by treatment. There was no effect of treatment (P = 0.37) or treatment by time (P = 0.19) on pregnancy, but there was a tendency (P = 0.13) for decreased embryonic loss among COMP heifers (27 ± 6%) compared to INORG heifers (38 ± 6%). There was a treatment by pregnancy status by time interaction (P < 0.01) on circulating PAG concentrations with PAG concentrations tending (P = 0.08) to be greater on day 25 among heifers in the COMP treatment compared to heifers in the INORG group. In summary, source of trace mineral did not affect puberty, RTS, pelvic area, or overall pregnancy success, but feeding complexed trace minerals tended to increase circulating PAG concentrations and embryo survival.
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Oligoelementos , Animais , Biomarcadores , Bovinos , Suplementos Nutricionais , Feminino , Inseminação Artificial/veterinária , Gravidez , Maturidade SexualRESUMO
Coenzyme Q (CoQ), a redox-active lipid essential for oxidative phosphorylation, is synthesized by virtually all cells, but how eukaryotes make the universal CoQ head group precursor 4-hydroxybenzoate (4-HB) from tyrosine is unknown. The first and last steps of this pathway have been defined in Saccharomyces cerevisiae, but the intermediates and enzymes involved in converting 4-hydroxyphenylpyruvate (4-HPP) to 4-hydroxybenzaldehyde (4-HBz) have not been described. Here, we interrogate this pathway with genetic screens, targeted LC-MS, and chemical genetics. We identify three redundant aminotransferases (Bna3, Bat2, and Aat2) that support CoQ biosynthesis in the absence of the established pathway tyrosine aminotransferases, Aro8 and Aro9. We use isotope labeling to identify bona fide tyrosine catabolites, including 4-hydroxyphenylacetate (4-HPA) and 4-hydroxyphenyllactate (4-HPL). Additionally, we find multiple compounds that rescue this pathway when exogenously supplemented, most notably 4-hydroxyphenylacetaldehyde (4-HPAA) and 4-hydroxymandelate (4-HMA). Finally, we show that the Ehrlich pathway decarboxylase Aro10 is dispensable for 4-HB production. These results define new features of 4-HB synthesis in yeast, demonstrate the redundant nature of this pathway, and provide a foundation for further study.
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Parabenos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transaminases/metabolismo , Tirosina/metabolismo , Ubiquinona/análogos & derivados , Oxirredução , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genética , Transaminases/genética , Ubiquinona/metabolismoRESUMO
One hundred and ninety non-lactating, pregnant beef cows (three-fourth Bos taurus and one-fourth Bos indicus; 138 multiparous and 52 primiparous) were assigned to this experiment at 117 ± 2.2 d of gestation (day 0). Cows were ranked by parity, pregnancy type (artificial insemination = 102 and natural service = 88), body weight (BW), and body condition score (BCS) and assigned to receive a supplement containing: 1) sulfate sources of Cu, Co, Mn, and Zn (INR; n = 95) or 2) an organic-complexed source of Cu, Mn, Co, and Zn (AAC; Availa 4; Zinpro Corporation, Eden Prairie, MN; n = 95). The INR and AAC provided the same daily amount of Cu, Co, Mn, and Zn, based on 7 g of the AAC source. From day 0 to calving, cows were maintained in a single pasture and were segregated three times weekly into 1 of the 24 individual feeding pens to receive treatments. Cow BW and BCS were recorded on days -30, 97, upon calving, and at weaning (day 367). Milk production was estimated at 42 ± 0.5 d postpartum via weigh-suckle-weigh (WSW) method. Liver biopsies were performed in 30 cows per treatment on days -30, 97, upon calving, and the day after WSW. Calf BW was recorded at birth and weaning. Liver and longissimus muscle (LM) biopsies were performed in 30 calves per treatment upon calving and 24 h later, the day after WSW, and at weaning. No treatment effects were detected (P ≥ 0.49) for cow BCS during gestation, despite AAC cows having greater (P = 0.04) BW on day 97. Liver Co concentrations were greater (P < 0.01) for AAC compared with INR cows, and liver concentrations of Cu were greater (P = 0.02) for INR compared with AAC cows on day 97. Upon calving, INR cows had greater (P ≤ 0.01) liver Cu and Zn concentrations compared with AAC cows. No other treatment differences were noted (P ≥ 0.17) for cow and calf liver trace mineral concentrations. Cows receiving AAC had greater (P = 0.04) hepatic mRNA expression of metallothionein 1A at calving, and their calves had greater (P = 0.04) hepatic mRNA expression of superoxide dismutase at weaning. Milk production did not differ between AAC and INR cows (P = 0.70). No treatment effects were detected (P ≥ 0.29) for mRNA expression of LM genes associated with adipogenic or muscle development activities in calves at birth and weaning. Calf birth and weaning BW also did not differ (P ≥ 0.19) between treatments. In summary, supplementing AAC or INR to beef cows during the last 5 mo of gestation yielded similar cow-calf productive responses until weaning.
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Ração Animal , Dieta , Ração Animal/análise , Animais , Bovinos , Dieta/veterinária , Suplementos Nutricionais , Feminino , Lactação , Gravidez , Desmame , ZincoRESUMO
One hundred and ninety nonlactating, pregnant beef cows (¾ Bos taurus and » Bos indicus; 138 multiparous and 52 primiparous) were assigned to this experiment at 117 ± 2.2 d of gestation (day 0). Cows were ranked by parity, pregnancy type (artificial insemination = 102, natural service = 88), body weight (BW) and body condition score, and assigned to receive a supplement containing: (1) sulfate sources of Cu, Co, Mn, and Zn (INR; n = 95) or (2) an organic complexed source of Cu, Mn, Co, and Zn (AAC; Availa4; Zinpro Corporation, Eden Prairie, MN; n = 95). The INR and AAC provided the same daily amount of Cu, Co, Mn, and Zn, based on 7 g of the AAC source. From day 0 to calving, cows were maintained in a single pasture and segregated 3 times weekly into 1 of 24 individual feeding pens to receive treatments. Calves were weaned on day 367 (200 ± 2 d of age), managed as a single group for a 45-d preconditioning period (days 367 to 412), and transferred to a single oat (Avena sativa L.) pasture on day 412. Heifer calves were moved to an adjacent oat pasture on day 437, where they remained until day 620. Heifer puberty status was verified weekly (days 437 to 619) based on plasma progesterone concentrations. Steer calves were shipped to a commercial feedlot on day 493, where they were managed as a single group until slaughter (day 724). Plasma cortisol concentration was greater (P = 0.05) in AAC calves at weaning but tended to be less (P = 0.10) on day 370 compared with INR calves. Mean plasma haptoglobin concentration was greater (P = 0.03) in INR vs. AAC calves during preconditioning, and no treatment effects were noted (P = 0.76) for preconditioning average daily gain (ADG). Puberty attainment was hastened in AAC heifers during the experiment (treatment × day; P < 0.01), despite similar (P = 0.39) ADG between treatments from days 412 to 620. Expression of myogenin mRNA in the longissimus muscle was greater (P = 0.05) in INR vs. AAC heifers on day 584. No treatment effects were detected (P ≥ 0.24) for steer ADG from day 412 until slaughter, nor for carcass quality traits. Hepatic mRNA expression of metallothionein 1A was greater (P = 0.02) in INR vs. AAC steers on day 586. In summary, supplementing Co, Cu, Zn, and Mn as organic complexed instead of sulfate sources to beef cows during the last 5 mo of gestation did not improve performance and physiological responses of the steer progeny until slaughter, but hastened puberty attainment in the female progeny reared as replacement heifers.
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Ração Animal , Dieta , Ração Animal/análise , Animais , Bovinos , Dieta/veterinária , Suplementos Nutricionais , Feminino , Gravidez , Maturidade Sexual , ZincoRESUMO
There is a critical need for adjuvants that can safely elicit potent and durable T cell-based immunity to intracellular pathogens. Here, we report that parenteral vaccination with a carbomer-based adjuvant, Adjuplex (ADJ), stimulated robust CD8 T-cell responses to subunit antigens and afforded effective immunity against respiratory challenge with a virus and a systemic intracellular bacterial infection. Studies to understand the metabolic and molecular basis for ADJ's effect on antigen cross-presentation by dendritic cells (DCs) revealed several unique and distinctive mechanisms. ADJ-stimulated DCs produced IL-1ß and IL-18, suggestive of inflammasome activation, but in vivo activation of CD8 T cells was unaffected in caspase 1-deficient mice. Cross-presentation induced by TLR agonists requires a critical switch to anabolic metabolism, but ADJ enhanced cross presentation without this metabolic switch in DCs. Instead, ADJ induced in DCs, an unique metabolic state, typified by dampened oxidative phosphorylation and basal levels of glycolysis. In the absence of increased glycolytic flux, ADJ modulated multiple steps in the cytosolic pathway of cross-presentation by enabling accumulation of degraded antigen, reducing endosomal acidity and promoting antigen localization to early endosomes. Further, by increasing ROS production and lipid peroxidation, ADJ promoted antigen escape from endosomes to the cytosol for degradation by proteasomes into peptides for MHC I loading by TAP-dependent pathways. Furthermore, we found that induction of lipid bodies (LBs) and alterations in LB composition mediated by ADJ were also critical for DC cross-presentation. Collectively, our model challenges the prevailing metabolic paradigm by suggesting that DCs can perform effective DC cross-presentation, independent of glycolysis to induce robust T cell-dependent protective immunity to intracellular pathogens. These findings have strong implications in the rational development of safe and effective immune adjuvants to potentiate robust T-cell based immunity.
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Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/fisiologia , Resinas Acrílicas/química , Adjuvantes Imunológicos/farmacologia , Apresentação de Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , NADPH Oxidase 2/fisiologia , Animais , Apresentação de Antígeno/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Despite the crucial roles of lipids in metabolism, we are still at the early stages of comprehensively annotating lipid species and their genetic basis. Mass spectrometry-based discovery lipidomics offers the potential to globally survey lipids and their relative abundances in various biological samples. To discover the genetics of lipid features obtained through high-resolution liquid chromatography-tandem mass spectrometry, we analysed liver and plasma from 384 diversity outbred mice, and quantified 3,283 molecular features. These features were mapped to 5,622 lipid quantitative trait loci and compiled into a public web resource termed LipidGenie. The data are cross-referenced to the human genome and offer a bridge between genetic associations in humans and mice. Harnessing this resource, we used genome-lipid association data as an additional aid to identify a number of lipids, for example gangliosides through their association with B4galnt1, and found evidence for a group of sex-specific phosphatidylcholines through their shared locus. Finally, LipidGenie's ability to query either mass or gene-centric terms suggests acyl-chain-specific functions for proteins of the ABHD family.
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Mapeamento Cromossômico , Genoma , Metabolismo dos Lipídeos/genética , Lipidômica , Lipídeos/química , Lipídeos/genética , Animais , Gangliosídeos/metabolismo , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hidrolases/genética , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/metabolismo , Fosfolipases A2/genética , Plasmídeos/genética , Caracteres SexuaisRESUMO
Degeneration of basal forebrain cholinergic circuitry represents an early event in the development of Alzheimer's disease (AD). These alterations in central cholinergic function are associated with disruptions in arousal, sleep/wake architecture, and cognition. Changes in sleep/wake architecture are also present in normal aging and may represent a significant risk factor for AD. M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs) have been reported to enhance cognition across preclinical species and may also provide beneficial effects for age- and/or neurodegenerative disease-related changes in arousal and sleep. In the present study, electroencephalography was conducted in young animals (mice, rats and nonhuman primates [NHPs]) and in aged mice to examine the effects of the selective M1 PAM VU0453595 in comparison with the acetylcholinesterase inhibitor donepezil, M1/M4 agonist xanomeline (in NHPs), and M1 PAM BQCA (in rats) on sleep/wake architecture and arousal. In young wildtype mice, rats, and NHPs, but not in M1 mAChR KO mice, VU0453595 produced dose-related increases in high frequency gamma power, a correlate of arousal and cognition enhancement, without altering duration of time across all sleep/wake stages. Effects of VU0453595 in NHPs were observed within a dose range that did not induce cholinergic-mediated adverse effects. In contrast, donepezil and xanomeline increased time awake in rodents and engendered dose-limiting adverse effects in NHPs. Finally, VU0453595 attenuated age-related decreases in REM sleep duration in aged wildtype mice. Development of M1 PAMs represents a viable strategy for attenuating age-related and dementia-related pathological disturbances of sleep and arousal.
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Doenças Neurodegenerativas , Roedores , Regulação Alostérica , Animais , Nível de Alerta , Camundongos , Primatas , Piridinas , Pirróis , Ratos , Receptor Muscarínico M1 , SonoRESUMO
Invited for this month's cover is the research team from the D.O.E. Great Lake Bioenergy Research Center (GLBRC) at the University of Wisconsin-Madison. The cover image shows how a diverse team with expertise in many different fields works together in an integrated fashion to address complex problems. Only when the whole system, from field to the liquid fuels and co-products, is assessed, can we identify the key parameters needed to design an economically viable biorefinery-based economy. Cover art by Chelsea Mamott. The Full Paper itself is available at 10.1002/cssc.201903345.
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BACKGROUND: Seizures are a common presenting sign in dogs with brain tumors. HYPOTHESIS/OBJECTIVES: To investigate the effect of radiotherapy on freedom from brain tumor-associated seizures and survival time in dogs. ANIMALS: Thirty-two client-owned dogs with brain tumor-associated seizures; 18 received medical treatment and radiotherapy, 14 received medical treatment alone. METHODS: Multicenter retrospective study. Baseline characteristics (seizure semiology, magnetic resonance imaging [MRI] characteristics, and treatment) and duration of seizure freedom were recorded for the 2 treatment groups. Duration of seizure freedom between groups was compared (log-rank test) using Cox's proportional hazard analysis, with baseline characteristics entered as covariates. RESULTS: The duration of seizure freedom and survival time were significantly longer in the radiotherapy group (P < .001), with a mean of 24 months (95% confidence interval [CI], 14.3-33.8) versus 1.7 months in the control group (95% CI, 0.5-2.9) and a mean of 34.6 months (95% CI: 25.2-44.1) versus 6.2 months in the control group (95% CI, 2.6-9.7) respectively. Baseline characteristics were not associated with duration of seizure freedom after the start of treatment. In the radiotherapy group, 5 dogs were euthanized during the study period because of causes other than seizures. In the control group, recurrence of seizures was observed before death in all dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: A longer period of seizure freedom and longer survival time was observed in dogs with brain tumors after radiotherapy compared to medical treatment only. The pathophysiological mechanisms of epileptogenesis and the effect of radiation therapy on seizure control are unclear to date. Further prospective studies are needed.
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Neoplasias Encefálicas/veterinária , Doenças do Cão/radioterapia , Glioma/veterinária , Recidiva Local de Neoplasia/veterinária , Convulsões/veterinária , Animais , Neoplasias Encefálicas/radioterapia , Doenças do Cão/mortalidade , Cães , Inglaterra/epidemiologia , Feminino , Glioma/radioterapia , Humanos , Masculino , Recidiva Local de Neoplasia/radioterapia , Propriedade , Registros/veterinária , Estudos Retrospectivos , Escócia/epidemiologia , Convulsões/epidemiologia , Inquéritos e Questionários , Análise de SobrevidaRESUMO
The hydroxycinnamic acids p-coumaric acid (pCA) and ferulic acid (FA) add diversity to the portfolio of products produced by using grass-fed lignocellulosic biorefineries. The level of lignin-bound pCA in Zea mays was modified by the alteration of p-coumaroyl-CoA monolignol transferase expression. The biomass was processed in a lab-scale alkaline-pretreatment biorefinery process and the data were used for a baseline technoeconomic analysis to determine where to direct future research efforts to couple plant design to biomass utilization processes. It is concluded that future plant engineering efforts should focus on strategies that ramp up accumulation of one type of hydroxycinnamate (pCA or FA) predominantly and suppress that of the other. Technoeconomic analysis indicates that target extraction titers of one hydroxycinnamic acid need to be >50â g kg-1 biomass, at least five times higher than observed titers for the impure pCA/FA product mixture from wild-type maize. The technical challenge for process engineers is to develop a viable process that requires more than 80 % reduction of the isolation costs.
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Utilization of both C5 and C6 sugars to produce biofuels and bioproducts is a key goal for the development of integrated lignocellulosic biorefineries. Previously we found that although engineered Zymomonas mobilis 2032 was able to ferment glucose to ethanol when fermenting highly concentrated hydrolyzates such as 9% glucan-loading AFEX-pretreated corn stover hydrolyzate (9% ACSH), xylose conversion after glucose depletion was greatly impaired. We hypothesized that impaired xylose conversion was caused by lignocellulose-derived inhibitors (LDIs) in hydrolyzates. To investigate the effects of LDIs on the cellular physiology of Z. mobilis during fermentation of hydrolyzates, including impacts on xylose utilization, we generated synthetic hydrolyzates (SynHs) that contained nutrients and LDIs at concentrations found in 9% ACSH. Comparative fermentations of Z. mobilis 2032 using SynH with or without LDIs were performed, and samples were collected for end product, transcriptomic, metabolomic, and proteomic analyses. Several LDI-specific effects were observed at various timepoints during fermentation including upregulation of sulfur assimilation and cysteine biosynthesis, upregulation of RND family efflux pump systems (ZMO0282-0285) and ZMO1429-1432, downregulation of a Type I secretion system (ZMO0252-0255), depletion of reduced glutathione, and intracellular accumulation of mannose-1P and mannose-6P. Furthermore, when grown in SynH containing LDIs, Z. mobilis 2032 only metabolized â¼50% of xylose, compared to â¼80% in SynH without LDIs, recapitulating the poor xylose utilization observed in 9% ACSH. Our metabolomic data suggest that the overall flux of xylose metabolism is reduced in the presence of LDIs. However, the expression of most genes involved in glucose and xylose assimilation was not affected by LDIs, nor did we observe blocks in glucose and xylose metabolic pathways. Accumulations of intracellular xylitol and xylonic acid was observed in both SynH with and without LDIs, which decreased overall xylose-to-ethanol conversion efficiency. Our results suggest that xylose metabolism in Z. mobilis 2032 may not be able to support the cellular demands of LDI mitigation and detoxification during fermentation of highly concentrated lignocellulosic hydrolyzates with elevated levels of LDIs. Together, our findings identify several cellular responses to LDIs and possible causes of impaired xylose conversion that will enable future strain engineering of Z. mobilis.
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The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.
Assuntos
Ácidos e Sais Biliares/metabolismo , Variação Biológica da População/genética , Microbioma Gastrointestinal/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Locos de Características Quantitativas/genética , Simportadores/genética , Akkermansia , Animais , Ácidos e Sais Biliares/sangue , Camundongos de Cruzamento Colaborativo , Feminino , Firmicutes/crescimento & desenvolvimento , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Modelos Animais , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Verrucomicrobia/crescimento & desenvolvimentoRESUMO
There are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated with a number of changes in the brain, including cognitive changes, effects on sleep, and effects on mood. These effects have been demonstrated in both rodent and non-human preclinical models. Furthermore, E2 interactions have been indicated in a number of neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. In normal brain aging, there are a number of systems that undergo changes and a number of these show interactions with E2, particularly the cholinergic system, the dopaminergic system, and mitochondrial function. E2 treatment has been shown to ameliorate some of the behavioral and morphological changes seen in preclinical models of menopause; however, in clinical populations, the effects of E2 treatment on cognitive changes after menopause are mixed. The future use of sex hormone treatment will likely focus on personalized or precision medicine for the prevention or treatment of cognitive disturbances during aging, with a better understanding of who may benefit from such treatment.
Assuntos
Encéfalo/metabolismo , Envelhecimento Cognitivo , Estrogênios/metabolismo , Animais , Encéfalo/fisiologia , Envelhecimento Cognitivo/fisiologia , Estrogênios/fisiologia , HumanosRESUMO
Judicious selection of mass spectrometry (MS) acquisition parameters is essential for effectively profiling the broad diversity and dynamic range of biomolecules. Typically, acquisition parameters are individually optimized to maximally characterize analytes from each new sample matrix. This time-consuming process often ignores the synergistic relationship between MS method parameters, producing suboptimal results. Here we detail the creation of an algorithm which accurately simulates LC-MS/MS lipidomic data acquisition performance for a benchtop quadrupole-Orbitrap MS system. By coupling this simulation tool with a genetic algorithm for constrained parameter optimization, we demonstrate the efficient identification of LC-MS/MS method parameter sets individually suited for specific sample matrices. Finally, we utilize the in silico simulation to examine how continued developments in MS acquisition speed and sensitivity will further increase the power of MS lipidomics as a vital tool for impactful biochemical analysis.