Methods to increase the amount of omega-3 (n–3) PUFAs in milk are desirable for neonatal health. The n–3 PUFA, α-linolenic acid (18:3n–3), can be elongated to EPA (20:5n–3) and DHA (22:6n–3). n–6 ...PUFAs suppress tissue n–3 PUFA incorporation, but the effect of SFAs is not clear.
In this study, we compared the effects of SFAs and n–6 PUFAs on n–3 PUFA incorporation into milk and tissues of lactating mice and tissues of their offspring.
Female CD-1 mice were bred at 8 wk of age. All experimental diets included 3% flaxseed oil and were begun on day 8 of lactation: low-fat diet (LFD); high-SFA diet (SAT), with an additional 12% saturated oil; or high-linoleic-acid diet (HLA), with 12% high-linoleic-acid oil (% kcal, carbohydrates:fat:protein: LFD, 49:24:27; both SAT and HLA, 35:46:19; n = 5/treatment). After 5 d, pup stomach milk clot FA profiles, tissue FA profiles in dams and pups, and mammary and hepatic expression of lipid metabolism genes in dams were analyzed. Data were analyzed by ANOVA with treatment diet as a fixed effect.
Dams in all groups had similar total milk fat concentrations, but both SAT and HLA decreased the concentration of n–3 PUFAs (SAT: −23%; HLA: −31%) compared with LFD, and HLA increased milk n–6 FAs by 347% compared with SAT. SAT pups had n–3 PUFA tissue concentrations similar to LFD, but HLA pups had lower n–3 PUFAs than SAT pups in multiple tissues (liver, −32%; kidney, −29%; heart, −28%; muscle, −18%). Mammary expression of lipid metabolism genes was mostly unchanged, but hepatic expression of elongases and desaturases was decreased with SAT compared with LFD elongation of very-long-chain fatty acid (Elov)5, −42%; Elov6, −64%; fatty acid desaturase (Fads)1, −33%; Fads2, −44%.
HLA decreased n–3 PUFA concentrations across multiple pup tissues compared with SAT. This suggests that high dietary n–6 PUFAs suppress n–3 PUFA incorporation in neonates.
Ponds are increasingly being constructed to enhance amenity values in human-dominated lowland landscapes, but little is known of design features that influence macroinvertebrates which can provide ...important food resources for fish and waterbirds. We quantified pond characteristics, sampled benthic and water-column macroinvertebrates in winter, and related abundance, biomass and community composition to characteristics of 34 ponds on the lower Waikato River floodplain, northern New Zealand. Compositionally different macroinvertebrate communities occupied water-column and benthic habitats. Landscape setting had a significant effect on benthic composition in terms of biomass, while the independent effects of frequency of pond drying or flooding, respectively, influenced benthic (abundance, biomass) or water-column (abundance) communities. Distance-based linear models highlighted physicochemical conditions, water depth regimes and riparian vegetation composition as key variables accounting for dissimilarity in total macroinvertebrate biomass between ponds. Our results indicate that managing hydrological stability of ponds in terms of permanence and flooding influences the composition and biomass of invertebrate communities. Within this hydrological template, design of appropriate depth regimes and riparian conditions can enhance accrual of macroinvertebrate biomass, thereby increasing food resources for fish and waterbirds.
Exposure to traffic-related air pollutants has been associated with increased risk of adverse cardiopulmonary outcomes and mortality; however, the biochemical pathways linking exposure to disease are ...not known. To delineate biological response mechanisms associated with exposure to near-highway ultrafine particles (UFP), we used untargeted high-resolution metabolomics to profile plasma from 59 participants enrolled in the Community Assessment of Freeway Exposure and Health (CAFEH) study. Metabolic variations associated with UFP exposure were assessed using a cross-sectional study design based upon low (mean 16,000 particles/cm
) and high (mean 24,000 particles/cm
) annual average UFP exposures. In comparing quantified metabolites, we identified five metabolites that were differentially expressed between low and high exposures, including arginine, aspartic acid, glutamine, cystine and methionine sulfoxide. Analysis of the metabolome identified 316 m/z features associated with UFP, which were consistent with increased lipid peroxidation, endogenous inhibitors of nitric oxide and vehicle exhaust exposure biomarkers. Network correlation analysis and metabolic pathway enrichment identified 38 pathways and included variations related to inflammation, endothelial function and mitochondrial bioenergetics. Taken together, these results suggest UFP exposure is associated with a complex series of metabolic variations related to antioxidant pathways, in vivo generation of reactive oxygen species and processes critical to endothelial function.
Intensive agriculture has resulted in the loss of biodiversity and the specialist flora and fauna associated with the semi-natural grasslands of low-intensity pastoral systems throughout northwest ...Europe. Techniques employed to restore and re-create these grasslands on agricultural land in the UK are reviewed. Extensive cutting and grazing management have been shown to diversify improved swards and facilitate re-colonisation on ex-arable soils, although rates of re-assembly of plant communities with affinity to existing semi-natural grasslands have generally been slow. On former agriculturally improved swards, nutrient depletion has accelerated this process, especially where “gaps” for establishment have been created. Similarly, on ex-arable soils “nutrient stripping” and sowing with diverse seed mixtures has led to the rapid development of species-rich swards. On free draining brown earths such an approach may be required to restore grassland communities where soil phosphorous concentrations exceed semi-natural levels by more than 10 mg/l (using Olsen's bicarbonate extractant). However, the appropriateness of this threshold for other soil types requires further sampling. Although restored grasslands are likely to contribute to national biodiversity targets success will ultimately depend on the reinstatement of the communities and ecological functions of semi-natural references. Although this is technically feasible for a few plant assemblages, less is known about the re-assembly of microbial and faunal communities, or the importance of trophic interactions during grassland succession. As a consequence, more research is required on the functional attributes of semi-natural grasslands, as well as the methods required to restore localised types, novel nutrient depletion techniques, the “phased” introduction of desirable but poor-performing species and the performance of different genotypes during grassland restoration.
Premedication for anxiety in adult day surgery Walker, Kevin J; Smith, Andrew F; Walker, Kevin J
Cochrane database of systematic reviews,
10/2009, Letnik:
2011, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Background
Since the early 1980s, it has become more and more common to carry out surgical procedures on a day case basis. Many patients are anxious before surgery yet there is sometimes a reluctance ...to provide sedative medication because it is believed to delay discharge from hospital.This is an updated version of the review first published in 2000 (previous updates 2003; 2006).
Objectives
To assess the effect of anxiolytic premedication on time to discharge in adult patients undergoing day case surgery under general anaesthesia.
Search methods
We identified trials by computerized searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2009 Issue 1 ); MEDLINE (1980 to January 2009); EMBASE (1980 to January 2009). We also checked the reference lists of trials and review articles and handsearched three main anaesthesia journals.
Selection criteria
We included all identified randomized controlled trials comparing anxiolytic drug(s) with placebo before general anaesthesia in adult day case surgical patients.
Data collection and analysis
We collected data on anaesthetic drugs used; results of psychomotor function tests where these were used to assess residual effect of premedication; and on times from end of anaesthesia to ability to walk unaided or readiness for discharge from hospital. Formal statistical synthesis of individual trials was not performed in view of the variety of drugs studied.
Main results
We included 17 studies. Methodological quality of included studies was poor. Of these 17, only seven studies specifically addressed the discharge question; none found any delay in premedicated patients. Two other studies used clinical criteria to assess fitness for discharge, though times were not given. Again, there was no difference from placebo. Eleven studies used tests of psychomotor function with or without clinical measures as indicators of recovery from anaesthesia. In none of these studies did the premedication appear to delay discharge, although performance on tests of psychomotor function was sometimes still impaired. Three studies showed no impairment in psychomotor function, six showed some impairment which had resolved by three hours or time of discharge and two showed significant impairment.
Authors' conclusions
We found no evidence of a difference in time to discharge from hospital, assessed by clinical criteria, in patients who received anxiolytic premedication. However, in view of the age and variety of anaesthetic techniques used and clinical heterogeneity between studies, inferences for current day case practice should be made with caution.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages that are more transmissible and resistant to currently approved antibody therapies poses a considerable ...challenge to the clinical treatment of coronavirus disease (COVID-19). Therefore, the need for ongoing discovery efforts to identify broadly reactive monoclonal antibodies to SARS-CoV-2 is of utmost importance. Here, we report a panel of SARS-CoV-2 antibodies isolated using the linking B cell receptor to antigen specificity through sequencing (LIBRA-seq) technology from an individual who recovered from COVID-19. Of these antibodies, 54042-4 shows potent neutralization against authentic SARS-CoV-2 viruses, including variants of concern (VOCs). A cryoelectron microscopy (cryo-EM) structure of 54042-4 in complex with the SARS-CoV-2 spike reveals an epitope composed of residues that are highly conserved in currently circulating SARS-CoV-2 lineages. Further, 54042-4 possesses uncommon genetic and structural characteristics that distinguish it from other potently neutralizing SARS-CoV-2 antibodies. Together, these findings provide motivation for the development of 54042-4 as a lead candidate to counteract current and future SARS-CoV-2 VOCs.
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•LIBRA-seq identifies 54042-4, a potently neutralizing SARS-CoV-2 antibody•54042-4 maintains potent neutralization against Alpha, Beta, Gamma, and Delta VOCs•The epitope of 54042-4 is highly conserved among current SARS-CoV-2 isolates
Kramer et al. demonstrate that antibody 54042-4 recognizes residues highly conserved across global SARS-CoV-2 isolates. Antibody 54042-4 potently neutralizes all known circulating variants of concern (VOCs) and could be developed as a clinical candidate to treat COVID-19 infection.
Cerebral cavernous malformation (CCM) is a hemorrhagic stroke disease affecting up to 0.5% of North Americans that has no approved nonsurgical treatment. A subset of patients have a hereditary form ...of the disease due primarily to loss-of-function mutations in KRIT1, CCM2, or PDCD10. We sought to identify known drugs that could be repurposed to treat CCM.
We developed an unbiased screening platform based on both cellular and animal models of loss of function of CCM2. Our discovery strategy consisted of 4 steps: an automated immunofluorescence and machine-learning-based primary screen of structural phenotypes in human endothelial cells deficient in CCM2, a secondary screen of functional changes in endothelial stability in these same cells, a rapid in vivo tertiary screen of dermal microvascular leak in mice lacking endothelial Ccm2, and finally a quaternary screen of CCM lesion burden in these same mice. We screened 2100 known drugs and bioactive compounds and identified 2 candidates, cholecalciferol (vitamin D3) and tempol (a scavenger of superoxide), for further study. Each drug decreased lesion burden in a mouse model of CCM vascular disease by ≈50%.
By identifying known drugs as potential therapeutics for CCM, we have decreased the time, cost, and risk of bringing treatments to patients. Each drug also prompts additional exploration of biomarkers of CCM disease. We further suggest that the structure-function screening platform presented here may be adapted and scaled to facilitate drug discovery for diverse loss-of-function genetic vascular disease.
Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased ...heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC).
We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I (
,
, and
) and HLA class -II loci (
,
, and
) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357).
Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97,
= 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95,
= 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87,
= 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant.
Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC.
Copper (Cu) is an essential metal for bacterial physiology but in excess it is bacteriotoxic. To limit Cu levels in the cytoplasm, most bacteria possess a transcriptionally responsive system for Cu ...export. In the Gram-positive human pathogen
(group A
GAS), this system is encoded by the
operon. This study demonstrates that although the site of GAS infection represents a Cu-rich environment, inactivation of the
Cu efflux gene does not reduce virulence in a mouse model of invasive disease.
, Cu treatment leads to multiple observable phenotypes, including defects in growth and viability, decreased fermentation, inhibition of glyceraldehyde-3-phosphate dehydrogenase (GapA) activity, and misregulation of metal homeostasis, likely as a consequence of mismetalation of noncognate metal-binding sites by Cu. Surprisingly, the onset of these effects is delayed by ∼4 h even though expression of
is upregulated immediately upon exposure to Cu. Further biochemical investigations show that the onset of all phenotypes coincides with depletion of intracellular glutathione (GSH). Supplementation with extracellular GSH replenishes the intracellular pool of this thiol and suppresses all the observable effects of Cu treatment. These results indicate that GSH buffers excess intracellular Cu when the transcriptionally responsive Cu export system is overwhelmed. Thus, while the
operon is responsible for Cu
, GSH has a role in Cu
and allows bacteria to maintain metabolism even in the presence of an excess of this metal ion.
The control of intracellular metal availability is fundamental to bacterial physiology. In the case of copper (Cu), it has been established that rising intracellular Cu levels eventually fill the metal-sensing site of the endogenous Cu-sensing transcriptional regulator, which in turn induces transcription of a copper export pump. This response caps intracellular Cu availability below a well-defined threshold and prevents Cu toxicity. Glutathione, abundant in many bacteria, is known to bind Cu and has long been assumed to contribute to bacterial Cu handling. However, there is some ambiguity since neither its biosynthesis nor uptake is Cu-regulated. Furthermore, there is little experimental support for this physiological role of glutathione beyond measuring growth of glutathione-deficient mutants in the presence of Cu. Our work with group A
provides new evidence that glutathione increases the threshold of intracellular Cu availability that can be tolerated by bacteria and thus advances fundamental understanding of bacterial Cu handling.
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