Gender-specific association of the K121Q Ectonucleotide Pyrophosphatase Phosphodiesterase (ENPP) 1 polymorphism with subcutaneous adiposity in a South African Black population

Purpose: This study aimed to determine whether the ENPP-1 K121Q (rs1044498) polymorphism was associated with adiposity and cardiometabolic disease markers within a South African Black population. Methods: Black participants from the greater Johannesburg–Soweto area in South Africa, for whom metabolic syndrome status, cardiometabolic disease markers, adipokine levels and body fat distribution had already been measured, were genotyped by PCR-RFLP for the presence of the K121Q polymorphism.Results: Within a cohort of 345 Black South Africans, the frequency of the ENPP-1 K121Q C allele was 0.89. In the total cohort, the K121Q polymorphism was not significantly associated with any cardiometabolic disease markers or adipokine levels. However, in the female population the CC genotype was shown to be associated with increased abdominal subcutaneous fat levels (p=0.007). Conclusion: This cohort of Black South Africans had a higher frequency of the C allele when compared to reported data for Asian and Caucasian populations, however this frequency was comparable to other African data. The presence of the rs1044498 polymorphism was not associated with markers of cardiometabolic disease, suggesting that these associations may be population dependent. The gender-specific genotypic association with subcutaneous fat levels is a novel finding requiring further investigation

Influence of Sward Height, Concentrate Supplementation and Season on Grazing Activity of Beef Cows

The influence of sward height, concentrate supplementation and season on daily pattern of forage consumption of lactating beef cows grazing cool season pastures was determined. Cows (n=24; BW=535±10.8 kg) were randomly assigned to eight plots maintained at sward heights (SH) of either 4-8 cm or 8-12 cm and fed three levels of concentrate supplement: none = 0 kg/day, low = 3.12 kg/day or high = 6.24 kg/day. Cows on lower SH had greater (P \u3c .08) forage dry matter intake and spent an additional 1.2 hours/day (P \u3c .01) grazing compared to the higher SH. Cows on lower SH consumed 7.7 kg/day of forage dry matter and grazed 9.4 hours/day whereas those on higher SH consumed 7.1 kg/day and grazed 8.2 hours/day. Cows on lower SH grazed 0.7 hours/day (P \u3c .06) and 0.4 hours/day (P \u3c .08) longer at 06:00-10:00 hour and 11:00-13:00 hour, respectively, compared to the higher SH. Grazing efficiency (kg of forage consumed/hour of grazing) decreased (P \u3c .01) as season progressed. Season influenced duration of grazing activity (P \u3c .01). Cows grazed 0.5 hours longer (P \u3c .01) at 06:00-10:00 hour late in summer (August) compared to spring (May) and mid summer (June/July). Cows grazed 0.3 hours longer (P \u3c .08) at 11:00-13:00 hour during spring compared to late summer

Sward Height; Visual Estimate Compared with Plate Meter Height

Sward height (SH) is widely used in pasture research and farm practice to evaluate pasture conditions. Visual estimates can take less time than actual measurements. This study compared visually estimated SH, of continuously grazed cool-season permanent pasture with plate meter height. Weekly estimates, by five people, were made on 12, 0.75 to 1 ha fields, grazed at two intensities. Paired data (visual estimate and plate meter height) were subjected to variance and covariance analyses and prediction equations were developed. Average visual height accounted for 86% of the variability in plate meter height. Inclusion of other sources of variability in the model (treatment, date and interactions) accounted for only a further 8% of the variability in plate meter height. On the basis of the strong linear relationships found between visual and plate meter heights, a procedure combining both methods is proposed that would reduce by 25% the time required to make weekly SH measurements of 12, 0.75 to 1 ha fields

Comparison of Two Low-Input Cow/Calf Production Systems on Temperate Grassland

Two systems of grass farming were compared in an eight-year experiment in West Virginia, USA. The grassland consisted primarily of cocksfoot (Dactylis glomerara L.), Kentucky bluegrass (Poa pratensis L.), tall fescue (Festuca arundinacea Schreb.), and red (Trifolium pretense L.) and white clover (T. repens L.). The objective was to compare two systems of beef cow calf production. The experiment was a randomized complete block with two replicated treatments. The grassland of treatment 1 (system 1) was overseeded with legumes, grazing started 1 wk earlier and continued 1 wk later than treatment 2 (system 2) and calves were allowed to forward creep graze. The hay land of treatment 2 received 56 kg N ha-1, at the start of the growing season. Response was measured as calf weaning weight, hay production, and pre-grazing herbage accumulation. Each treatment/replicate (experimental unit) was assigned 6.5 ha divided into three grassland managements units: pasture, buffer and meadow. Pasture was grazed and not cut for hay. First growth of buffer and meadow was harvested as hay. Subsequently, buffer was grazed, meadow was again harvested, followed by late season grazing. Management units were divided into four paddocks. Animals occupied a paddock for 7 days resulting in 4-week grazing cycles from May to mid-November. Eight cow/calf pairs grazed each treatment/replicate (stocking rate 1.23 cow calves ha-1 ). Calves, born in March, were weaned in late September. System 1 calves gained 1.18 kg dy-1 (P \u3c 0.04 SE=0.01) compared with those on System 2 which gained 1.14 kg dy-1. Annual hay production on System 2 was 5784 kg ha-1, significantly more than on System 1 (P \u3c 0.01 SE=107). However, in System 1 extending the grazing season reduced the amount of hay required annually by 1680 kg ha-1. System 1 hay had a greater proportion of legume (9 vs. 3%, P \u3c 0.01 SE=0.5) and a lesser proportion of grass (75 vs. 85%, P \u3c 0.01 SE=0.7) than those of system 2

The Microbial Opsin Family of Optogenetic Tools

The capture and utilization of light is an exquisitely evolved process. The single-component microbial opsins, although more limited than multicomponent cascades in processing, display unparalleled compactness and speed. Recent advances in understanding microbial opsins have been driven by molecular engineering for optogenetics and by comparative genomics. Here we provide a Primer on these light-activated ion channels and pumps, describe a group of opsins bridging prior categories, and explore the convergence of molecular engineering and genomic discovery for the utilization and understanding of these remarkable molecular machines.National Institutes of Health (U.S.) (TR01)Bill & Melinda Gates FoundationSimons FoundationDamon Runyon Cancer Research FoundationMcKnight FoundationRobert MetcalfeHelen S. Boylan Foundatio

Supplemental Ascorbate Diminishes DNA Damage Yet Depletes Glutathione and Increases Acute Liver Failure in a Mouse Model of Hepatic Antioxidant System Disruption

Cellular oxidants are primarily managed by the thioredoxin reductase-1 (TrxR1)- and glutathione reductase (Gsr)-driven antioxidant systems. In mice having hepatocyte-specific codisruption of TrxR1 and Gsr (TrxR1/Gsr-null livers), methionine catabolism sustains hepatic levels of reduced glutathione (GSH). Although most mice with TrxR1/Gsr-null livers exhibit long-term survival, ~25% die from spontaneous liver failure between 4- and 7-weeks of age. Here we tested whether liver failure was ameliorated by ascorbate supplementation. Following ascorbate, dehydroascorbate, or mock treatment, we assessed survival, liver histology, or hepatic redox markers including GSH and GSSG, redox enzyme activities, and oxidative damage markers. Unexpectedly, rather than providing protection, ascorbate (5 mg/mL, drinking water) increased the death-rate to 43%. In adults, ascorbate (4 mg/g × 3 days i.p.) caused hepatocyte necrosis and loss of hepatic GSH in TrxR1/Gsr-null livers but not in wildtype controls. Dehydroascorbate (0.3 mg/g i.p.) also depleted hepatic GSH in TrxR1/Gsr-null livers, whereas GSH levels were not significantly affected by either treatment in wildtype livers. Curiously, however, despite depleting GSH, ascorbate treatment diminished basal DNA damage and oxidative stress markers in TrxR1/Gsr-null livers. This suggests that, although ascorbate supplementation can prevent oxidative damage, it also can deplete GSH and compromise already stressed livers

scMRI Reveals Large-Scale Brain Network Abnormalities in Autism

Autism is a complex neurological condition characterized by childhood onset of dysfunction in multiple cognitive domains including socio-emotional function, speech and language, and processing of internally versus externally directed stimuli. Although gross brain anatomic differences in autism are well established, recent studies investigating regional differences in brain structure and function have yielded divergent and seemingly contradictory results. How regional abnormalities relate to the autistic phenotype remains unclear. We hypothesized that autism exhibits distinct perturbations in network-level brain architecture, and that cognitive dysfunction may be reflected by abnormal network structure. Network-level anatomic abnormalities in autism have not been previously described. We used structural covariance MRI to investigate network-level differences in gray matter structure within two large-scale networks strongly implicated in autism, the salience network and the default mode network, in autistic subjects and age-, gender-, and IQ-matched controls. We report specific perturbations in brain network architecture in the salience and default-mode networks consistent with clinical manifestations of autism. Extent and distribution of the salience network, involved in social-emotional regulation of environmental stimuli, is restricted in autism. In contrast, posterior elements of the default mode network have increased spatial distribution, suggesting a ‘posteriorization’ of this network. These findings are consistent with a network-based model of autism, and suggest a unifying interpretation of previous work. Moreover, we provide evidence of specific abnormalities in brain network architecture underlying autism that are quantifiable using standard clinical MRI

Discrimination of Potent Inhibitors of Toxoplasma gondii Enoyl-Acyl Carrier Protein Reductase by a Thermal Shift Assay

Many microbial pathogens rely on a type II fatty acid synthesis (FASII) pathway that is distinct from the type I pathway found in humans. Enoyl-acyl carrier protein reductase (ENR) is an essential FASII pathway enzyme and the target of a number of antimicrobial drug discovery efforts. The biocide triclosan is established as a potent inhibitor of ENR and has been the starting point for medicinal chemistry studies. We evaluated a series of triclosan analogues for their ability to inhibit the growth of Toxoplasma gondii, a pervasive human pathogen, and its ENR enzyme (TgENR). Several compounds that inhibited TgENR at low nanomolar concentrations were identified but could not be further differentiated because of the limited dynamic range of the TgENR activity assay. Thus, we adapted a thermal shift assay (TSA) to directly measure the dissociation constant (Kd) of the most potent inhibitors identified in this study as well as inhibitors from previous studies. Furthermore, the TSA allowed us to determine the mode of action of these compounds in the presence of the reduced nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide (NAD+) cofactor. We found that all of the inhibitors bind to a TgENR–NAD+ complex but that they differed in their dependence on NAD+ concentration. Ultimately, we were able to identify compounds that bind to the TgENR–NAD+ complex in the low femtomolar range. This shows how TSA data combined with enzyme inhibition, parasite growth inhibition data, and ADMET predictions allow for better discrimination between potent ENR inhibitors for the future development of medicine