Testing quantum electrodynamics in extreme fields using helium-like uranium.

Quantum electrodynamics (QED), the quantum field theory that describes the interaction between light and matter, is commonly regarded as the best-tested quantum theory in modern physics. However, this claim is mostly based on extremely precise studies performed in the domain of relatively low field strengths and light atoms and ions1-6. In the realm of very strong electromagnetic fields such as in the heaviest highly charged ions (with nuclear charge Z ≫ 1), QED calculations enter a qualitatively different, non-perturbative regime. Yet, the corresponding experimental studies are very challenging, and theoretical predictions are only partially tested. Here we present an experiment sensitive to higher-order QED effects and electron-electron interactions in the high-Z regime. This is achieved by using a multi-reference method based on Doppler-tuned X-ray emission from stored relativistic uranium ions with different charge states. The energy of the 1s1/22p3/2 J = 2 → 1s1/22s1/2 J = 1 intrashell transition in the heaviest two-electron ion (U90+) is obtained with an accuracy of 37 ppm. Furthermore, a comparison of uranium ions with different numbers of bound electrons enables us to disentangle and to test separately the one-electron higher-order QED effects and the bound electron-electron interaction terms without the uncertainty related to the nuclear radius. Moreover, our experimental result can discriminate between several state-of-the-art theoretical approaches and provides an important benchmark for calculations in the strong-field domain.

Notch Signaling Plays a Dual Role in Regulating the Neuron-to-Oligodendrocyte Switch in the Developing Dorsal Forebrain.

Neural progenitor cells in the developing dorsal forebrain generate excitatory neurons followed by oligodendrocytes (OLs) and astrocytes. However, the specific mechanisms that regulate the timing of this neuron-glia switch are not fully understood. In this study, we show that the proper balance of Notch signaling in dorsal forebrain progenitors is required to generate oligodendrocytes during late stages of embryonic development. Using ex vivo and in utero approaches in mouse embryos of both sexes, we found that Notch inhibition reduced the number of oligodendrocyte lineage cells in the dorsal pallium. However, Notch overactivation also prevented oligodendrogenesis and maintained a progenitor state. These results point toward a dual role for Notch signaling in both promoting and inhibiting oligodendrogenesis, which must be fine-tuned to generate oligodendrocyte lineage cells at the right time and in the right numbers. We further identified the canonical Notch downstream factors HES1 and HES5 as negative regulators in this process. CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-mediated knockdown of Hes1 and Hes5 caused increased expression of the pro-oligodendrocyte factor ASCL1 and led to precocious oligodendrogenesis. Conversely, combining Notch overactivation with ASCL1 overexpression robustly promoted oligodendrogenesis, indicating a separate mechanism of Notch that operates synergistically with ASCL1 to specify an oligodendrocyte fate. We propose a model in which Notch signaling works together with ASCL1 to specify progenitors toward the oligodendrocyte lineage but also maintains a progenitor state through Hes-dependent repression of Ascl1 so that oligodendrocytes are not made too early, thus contributing to the precise timing of the neuron-glia switch.SIGNIFICANCE STATEMENT Neural progenitors make oligodendrocytes after neurogenesis starts to wind down, but the mechanisms that control the timing of this switch are poorly understood. In this study, we identify Notch signaling as a critical pathway that regulates the balance between progenitor maintenance and oligodendrogenesis. Notch signaling is required for the oligodendrocyte fate, but elevated Notch signaling prevents oligodendrogenesis and maintains a progenitor state. We provide evidence that these opposing functions are controlled by different mechanisms. Before the switch, Notch signaling through Hes factors represses oligodendrogenesis. Later, Notch signaling through an unknown mechanism promotes oligodendrogenesis synergistically with the transcription factor ASCL1. Our study underscores the complexity of Notch and reveals its importance in regulating the timing and numbers of oligodendrocyte production.

The contribution of cannabis use to the increased psychosis risk among minority ethnic groups in Europe.

BACKGROUND: We examined whether cannabis use contributes to the increased risk of psychotic disorder for non-western minorities in Europe. METHODS: We used data from the EU-GEI study (collected at sites in Spain, Italy, France, the United Kingdom, and the Netherlands) on 825 first-episode patients and 1026 controls. We estimated the odds ratio (OR) of psychotic disorder for several groups of migrants compared with the local reference population, without and with adjustment for measures of cannabis use. RESULTS: The OR of psychotic disorder for non-western minorities, adjusted for age, sex, and recruitment area, was 1.80 (95% CI 1.39-2.33). Further adjustment of this OR for frequency of cannabis use had a minimal effect: OR = 1.81 (95% CI 1.38-2.37). The same applied to adjustment for frequency of use of high-potency cannabis. Likewise, adjustments of ORs for most sub-groups of non-western countries had a minimal effect. There were two exceptions. For the Black Caribbean group in London, after adjustment for frequency of use of high-potency cannabis the OR decreased from 2.45 (95% CI 1.25-4.79) to 1.61 (95% CI 0.74-3.51). Similarly, the OR for Surinamese and Dutch Antillean individuals in Amsterdam decreased after adjustment for daily use: from 2.57 (95% CI 1.07-6.15) to 1.67 (95% CI 0.62-4.53). CONCLUSIONS: The contribution of cannabis use to the excess risk of psychotic disorder for non-western minorities was small. However, some evidence of an effect was found for people of Black Caribbean heritage in London and for those of Surinamese and Dutch Antillean heritage in Amsterdam.

Sperm characteristics of cryopreserved Prochilodus lineatus semen after adding cholesterol-loaded cyclodextrin.

The experiment evaluated the effect of adding cholesterol-loaded cyclodextrin (CLC) to Prochilodus lineatus fish (Curimata) semen on post-thaw sperm quality. Twelve adult fish were used for sperm collection after induced spermiation with carp pituitary gland. The semen was diluted and treated with CLC in concentrations of 0 (control), 0.5, 1.0, 2.0, 3.0, and 4.0 mg for 120 × 106 spermatozoa/ml, loaded in 0.5 ml straws, packaged and placed in dry vapor vessel cylinders for 24 h before being submerged in liquid nitrogen for storage. The samples were thawed in a water bath at 60 °C for 8 s, and the sperm parameters evaluated were motility, activation duration, longevity, plasma membrane integrity, and morphology. Data were tested for normal distribution and ANOVA, followed by Friedman test (P < 0.05). Spermatozoa treated with CLC displayed higher motility than the control (P < 0.05). The duration of sperm activation was longer in sperm treated with 0.5, 1.0, and 2.0 mg of CLC than in control (P < 0.05). The membrane integrity was higher in sperm treated with 0.5, 1.0, 2.0, and 3.0 mg of CLC than in control and four mg-treated samples (P < 0.05). The sperm longevity and morphology alterations did not differ between treatments (P > 0.05). Adding 0.5, 1.0, or 2.0 mg of CLC in Prochilodus lineatus semen before cryopreservation improves sperm motility and membrane integrity.

Graduate Student Literature Review: Exploring choline's important roles as a nutrient for transition dairy cows.

In late gestation and in the first weeks postpartum, lipid droplets accumulate in the hepatic tissue resulting in approximately 40% to 50% of the dairy cows developing hepatic lipidosis in the first weeks of lactation. Elevated concentrations of triacylglycerol in the hepatic tissue are associated with increased risk of peripartum diseases and impaired productive performance. Cows with hepatic lipidosis need to dispose the excess of hepatic triacylglycerol, but this is a slow process in the bovine liver and relies on primary mechanisms such as complete oxidation and ketogenesis because of the limited export of triacylglycerols as lipoproteins. Choline is a lipotropic compound because, among other functions, it facilitates the export of lipids from the liver. Supplementing choline as rumen-protected choline (RPC) to diets of feed-restricted dairy cows reduces the degree of triacylglycerol infiltration into the hepatic parenchyma in part by enhancing export of triacylglycerol as nascent lipoprotein. The reduced accumulation of triacylglycerol in hepatic tissue in feed-restricted cows fed RPC might affect secondary pathways involved in hepatic disposal of fatty acids such as increased cellular autophagy and lipophagy and minimize endoplasmic reticulum stress response and hepatocyte inflammation. Collectively, these effects on secondary pathways might further reduce the severity of hepatic lipidosis in cows. One of the benefits of supplementing RPC is improved fat digestibility, perhaps because choline, through phosphatidylcholines, facilitates lipid transport within the enterocyte by increasing the synthesis of chylomicrons. Finally, when supplemented during the transition period, RPC improves productive performance of cows, irrespective of their body condition, that extends well beyond the period of supplementation. This review summarizes the current understanding of hepatic lipidosis in early lactation, recapitulates the absorption, transport and metabolism of choline, and discusses its role on hepatic metabolism and gastrointestinal functions, which collectively results in improved performance in dairy cows.

Dietary supplementation of rumen native microbes improves lactation performance and feed efficiency in dairy cows.

Objectives were to determine the effects of 2 dietary microbial additives supplemented to diets of Holstein cows on productive performance and feed efficiency. One-hundred and 17 Holstein cows were enrolled at 61 d (31 to 87 d) postpartum in a randomized complete block design experiment. Cows were blocked by parity group, as nulliparous or multiparous cows and, within parity, by pre-treatment energy-corrected milk yield. Within block, cows were randomly assigned to one of 3 treatments administered as top-dress for 140 d. Treatments consisted of either 100 g of corn meal containing no microbial additive (CON; 15 primiparous and 25 multiparous), 100 g of corn meal containing 5 g of a mixture of Clostridium beijerinckii and Pichia kudriavzevii (G1; 4 × 107 cfu of C. beijerinckii and 1 × 109 cfu of P. kudriavzevii; 14 primiparous and 24 multiparous), or 100 g of corn meal containing 5 g of a mixture of C. beijerinckii, P. kudriavzevii, Butyrivibrio fibrisolvens, and Ruminococcus bovis (G2; 4 × 107 cfu of C. beijerinckii, 1 × 109 cfu of P. kudriavzevii, 1 × 108 cfu of B. fibrisolvens, and 1 × 108 cfu of R. bovis; 15 primiparous and 24 multiparous). Intake of DM, milk yield, and BW were measured daily, whereas milk composition was analyzed at each milking 2 d a week, and body condition was scored twice weekly. Milk samples were collected on d 60 and 62 in the experiment and analyzed for individual fatty acids. The data were analyzed with mixed-effects models with orthogonal contrast to determine the impact of microbial additive (MA; CON vs. 1/2 G1 + 1/2 G2) and type of microbial additive (TMA; G1 vs. G2). Results are described in sequence as CON, G1, and G2. Intake of DM (22.2 vs. 22.4 vs. 22.4 kg/d), BW (685 vs. 685 vs. 685 kg) and the daily BW change (0.40 vs. 0.39 vs. 0.39 kg/d) did not differ among treatments; however, feeding MA tended to increase BCS (3.28 vs. 3.33 vs. 3.36). Supplementing MA increased yields of milk (39.9 vs. 41.3 vs. 41.5 kg/d), ECM (37.9 vs. 39.3 vs. 39.9 kg/d), fat (1.31 vs. 1.37 vs. 1.40 kg/d), total solids (4.59 vs. 4.75 vs. 4.79 kg/d), and ECM per kg of DMI (1.72 vs. 1.76 vs. 1.80 kg/kg). Furthermore, cows fed MA increased yields of pre-formed fatty acids in milk fat (>16C; 435 vs. 463 vs. 488 g/d), particularly unsaturated fatty acids (367 vs. 387 vs. 410 g/d), such as linoleic (C18:2 cis-9, cis-12; 30.9 vs. 33.5 vs. 35.4 g/d) and α-linolenic acids (C18:3 cis-9, cis-12, cis-15; 2.46 vs. 2.68 vs. 2.82 g/d) on d 60 and 62 in the experiment. Collectively, supplementing G1 and G2 improved productive performance of cows with no differences between the 2 MA.

Assessing different cross-validation schemes for predicting novel traits using sensor data: an application to dry matter intake and residual feed intake using milk spectral data.

Feed efficiency is important for economic profitability of dairy farms; however, recording daily dry matter intakes (DMI) is expensive. Our objective was to investigate the potential use of milk mid-infrared (MIR) spectral data to predict proxy phenotypes for DMI based on different cross-validation schemes. We were specifically interested in comparisons between a model that included only MIR data (Model M1), a model that incorporated different energy sink predictors, such as body weight, body weight change, and milk energy (Model M2), and an extended model that incorporated both energy sinks and MIR data (Model M3). Models M2 and M3 also included various cow level variables (stage of lactation, age at calving, parity) such that any improvement in model performance from M2 to M3, whether through a smaller root mean squared error (RMSE) or a greater squared predictive correlation (R2), could indicate a potential benefit of MIR to predict residual feed intake. The data used in our study originated from a multi-institutional project on the genetics of feed efficiency in US Holsteins. Analyses were conducted on 2 different trait definitions based on different period lengths: averaged across weeks vs. averaged across 28-d. Specifically, there were 19,942 weekly records on 1,812 cows across 46 experiments or cohorts and 3,724 28-d records on 1,700 cows across 43 different cohorts. The cross-validation analyses involved 3 different k-fold schemes. First, a 10-fold cow-independent cross-validation was conducted whereby all records from any one cow were kept together in either training or test sets. Similarly, a 10-fold experiment-independent cross-validation kept entire experiments together whereas a 4-fold herd-independent cross-validation kept entire herds together in either training or test sets. Based on cow-independent cross-validation for both weekly and 28-d DMI, adding MIR predictors to energy sinks (Models M3 vs M2) significantly (P < 10-10) reduced average RMSE to 1.59 kg and increased average R2 to 0.89. However, adding MIR to energy sinks (M3) to predict DMI either within an experiment-independent or herd-independent cross-validation scheme seemed to demonstrate no merit (P > 0.05) compared with an energy sink model (M2) for either R2 or RMSE (respectively, 0.68 and 2.55 kg for M2 in herd-independent scheme). We further noted that with broader cross-validation schemes, i.e., from cow-independent to experiment-independent to herd-independent schemes, the mean and slope bias increased. Given that proxy DMI phenotypes for cows would need to be almost entirely generated in herds having no DMI or training data of their own, herd-independent cross-validation assessments of predictive performance should be emphasized. Hence, more research on predictive algorithms suitable for broader cross-validation schemes and a more earnest effort on calibration of spectrophotometers against each other should be considered.

Unknown parent groups and truncated pedigree in single-step genomic evaluations of Murrah buffaloes.

Missing pedigree may produce bias in genomic evaluations. Thus, strategies to deal with this problem have been proposed as using unknown parent groups (UPG) or truncated pedigrees. The aim of this study was to investigate the impact of modeling missing pedigree under ssGBLUP evaluations for productive and reproductive traits in dairy buffalos using different approaches: 1) traditional BLUP without UPG (BLUP), 2) traditional BLUP including UPG (BLUP/UPG), 3) ssGBLUP without UPG (ssGBLUP), 4) ssGBLUP including UPG in the A and A22 matrices (ssGBLUP/A_UPG), 5) ssGBLUP including UPG in all elements of the H matrix (ssGBLUP/H_UPG), 6) BLUP with pedigree truncation for the last 3 generations (BLUP/truncated), and 7) ssGBLUP with pedigree truncation for the last 3 generations (ssGBLUP/ truncated). UPGs were not used in the scenarios with truncated pedigree. A total of 3,717, 4,126 and 3,823 records of the first lactation for accumulated 305 d milk yield (MY), age at first calving (AFC) and lactation length (LL), respectively were used. Accuracies ranged from 0.27 for LL (BLUP) to 0.46 for MY (BLUP), bias ranged from -0.62 for MY (ssGBLUP) to 0.0002 for AFC (BLUP/truncated), and dispersion ranged from 0.88 for MY (BLUP/ A_UPG) to 1.13 for LL (BLUP). Genetic trend showed genetic gains for all traits across 20 years of selection and the impact of including either genomic information, UPG or pedigree truncation under GEBV accuracies ranged among the evaluated traits. Overall, methods using UPGs, truncation pedigree and genomic information exhibited potential to improve GEBV accuracies, bias and dispersion for all traits compared with other methods. Truncated scenarios promoted high genetic gains. In small populations with few genotyped animals, combining truncated pedigree or UPG with genomic information is a feasible approach to deal with missing pedigrees.

Estimation of genetic parameters for feed efficiency traits using random regression models in dairy cattle.

Feed efficiency has become an increasingly important research topic in recent years. As feed costs rise and the environmental impacts of agriculture become more apparent, improving the efficiency with which dairy cows convert feed to milk is increasingly important. However, feed intake is expensive to measure accurately on large populations, making the inclusion of this trait in breeding programs difficult. Understanding how the genetic parameters of feed efficiency and traits related to feed efficiency vary throughout the lactation period is valuable to gain understanding into the genetic nature of feed efficiency. This study used 121,226 dry matter intake (DMI) records, 120,500 energy-corrected milk (ECM) records, and 98,975 metabolic body weight (MBW) records, collected on 7,440 first-lactation Holstein cows from 6 countries (Canada, Denmark, Germany, Spain, Switzerland, and the United States), from January 2003 to February 2022. Genetic parameters were estimated using a multiple-trait random regression model with a fourth-order Legendre polynomial for all traits. Weekly phenotypes for DMI were re-parameterized using linear regressions of DMI on ECM and MBW, creating a measure of feed efficiency that was genetically corrected for ECM and MBW, referred to as genomic residual feed intake (gRFI). Heritability (SE) estimates varied from 0.15 (0.03) to 0.29 (0.02) for DMI, 0.24 (0.01) to 0.29 (0.03) for ECM, 0.55 (0.03) to 0.83 (0.05) for MBW, and 0.12 (0.03) to 0.22 (0.06) for gRFI. In general, heritability estimates were lower in the first stage of lactation compared with the later stages of lactation. Additive genetic correlations between weeks of lactation varied, with stronger correlations between weeks of lactation that were close together. The results of this study contribute to a better understanding of the change in genetic parameters across the first lactation, providing insight into potential selection strategies to include feed efficiency in breeding programs.

Association between prepartum body condition score and prepartum and postpartum dry matter intake and energy balance in multiparous Holstein cows.

The objectives of this retrospective observational study were to investigate the association between BCS at 21 d before calving with prepartum and postpartum DMI, energy balance (EB), and milk yield. Data from 427 multigravid cows from 11 different experiments conducted at the University of Florida (Gainesville, FL) were used. Cows were classified according to their BCS at 21 d before calving as fat (BCS ≥ 4.00; n = 83), moderate (BCS = 3.25-3.75; n = 287), and thin (BCS ≤ 3.00; n = 57). Daily DMI from -21 to -1 and from +1 to +28 DIM was individually recorded. Energy balance was calculated as the difference between net energy for lactation consumed and required. Dry matter intake in fat cows was lower than that in moderate and thin cows both prepartum (fat = 9.97 ± 0.21, moderate = 11.15 ± 0.14, and thin = 11.92 ± 0.22 kg/d) and postpartum (fat = 14.35 ± 0.49, moderate = 15.47 ± 0.38, and thin = 16.09 ± 0.47 kg/d). Dry matter intake was also lower for moderate cows compared with thin cows prepartum, but not postpartum. Energy balance in fat cows was lower than in moderate and thin cows both prepartum (fat = -4.16 ± 0.61, moderate = -1.20 ± 0.56, and thin = 0.88 ± 0.62 Mcal/d) and postpartum (fat = -12.77 ± 0.50, moderate = -10.13 ± 0.29, and thin = -6.14 ± 0.51 Mcal/d). Energy balance was also lower for moderate cows compared with thin cows both prepartum and postpartum. There was a quadratic association between BCS at 21 d before calving and milk yield. Increasing BCS from 2.5 to 3.5 was associated with an increase in daily milk yield of 6.0 kg and 28 d cumulative milk of 147 kg. Increasing BCS from 3.5 to 4.5 was associated with a decrease in daily milk yield of 4.4 kg and 28 d cumulative milk of 116 kg. In summary, a moderate BCS at 21 d before calving was associated with intermediate DMI and EB pre- and postpartum but greater milk yield compared with thinner and fatter cows. Our findings indicate that a moderate BCS is ideal for ensuring a successful lactation.

Application of behavior data to predictive exploratory models of metritis self-cure and treatment failure in dairy cows.

The objective was to evaluate the performance of exploratory models containing routinely available on-farm data, behavior data, and the combination of both to predict metritis self-cure (SC) and treatment failure (TF). Holstein cows (n = 1,061) were fitted with a collar-mounted automated-health monitoring device (AHMD) from -21 ± 3 to 60 ± 3 d relative to calving to monitor rumination time and activity. Cows were examined for diagnosis of metritis at 4 ± 1, 7 ± 1, and 9 ± 1 d in milk (DIM). Cows diagnosed with metritis (n = 132), characterized by watery, fetid, reddish/brownish vaginal discharge (VD), were randomly allocated to 1 of 2 treatments: control (CON; n = 62), no treatment at the time of metritis diagnosis (d 0); or ceftiofur (CEF; n = 70), subcutaneous injection of 6.6 mg/kg of ceftiofur crystalline-free acid on d 0 and 3 relative to diagnosis. Cure was determined 12 d after diagnosis and was considered when VD became mucoid and not fetid. Cows in CON were used to determine SC, and cows in CEF were used to determine TF. Univariable analyses were performed using farm-collected data (parity, calving season, calving-related disorders, body condition score, rectal temperature, and DIM at metritis diagnosis) and behavior data (i.e., daily averages of rumination time, activity generated by AHMD, and derived variables) to assess their association with metritis SC or TF. Variables with P-values ≤0.20 were included in the multivariable logistic regression exploratory models. To predict SC, the area under the curve (AUC) for the exploratory model containing only data routinely available on-farm was 0.75. The final exploratory model to predict SC combining routinely available on-farm data and behavior data increased the AUC to 0.87, with sensitivity (Se) of 89% and specificity (Sp) of 77%. To predict TF, the AUC for the exploratory model containing only data routinely available on-farm was 0.90. The final exploratory model combining routinely available on-farm data and behavior data increased the AUC to 0.93, with Se of 93% and Sp of 87%. Cross-validation analysis revealed that generalizability of the exploratory models was poor, which indicates that the findings are applicable to the conditions of the present exploratory study. In summary, the addition of behavior data contributed to increasing the prediction of SC and TF. Developing and validating accurate prediction models for SC could lead to a reduction in antimicrobial use, whereas accurate prediction of cows that would have TF may allow for better management decisions.

Evaluating differences in milk production, reproductive performance, and survival associated with vaginal discharge characteristics and fever in postpartum dairy cows.

The objective was to assess differences in productive and reproductive performance, and survival associated with vaginal discharge characteristics and fever in postpartum dairy cows located in Western and Southern states of the U.S.A. This retrospective cohort study included data from 3 experiments conducted in 9 dairies. Vaginal discharge was evaluated twice within 12 DIM and scored on a 5-point scale. The highest score observed for each cow was used for group assignment (VD group) as follows: VD 1 and 2 (VD 1/2; n = 1,174) = clear mucus/lochia with or without flecks of pus; VD 3 (n = 1,802) = mucopurulent with < 50% pus; VD 4 (n = 1,643) = mucopurulent with ≥50% of pus or non-fetid reddish/brownish mucous, n = 1,643; VD 5 = fetid, watery, and reddish/brownish, n = 1,800. All VD 5 cows received treatment according to each herd's protocol. Rectal temperature was assessed in a subset of VD 5 cows, and subsequently divided into Fever (rectal temperature ≥39.5°C; n = 334) and NoFever (n = 558) groups. A smaller proportion of cows with VD 5 (67.6%) resumed ovarian cyclicity compared with VD 1/2 (76.2%) and VD 4 (72.9%) cows; however, a similar proportion of VD5 and VD 3 (72.6%) cows resumed ovarian cyclicity. A smaller proportion of VD 5 (85.8%) cows received at least one artificial insemination (AI) compared with VD 1/2 (91.5%), VD 3 (91.0%), or VD 4 (91.6%) cows. Although we did not detect differences in pregnancy at first AI according to VD, fewer cows with VD 5 (64.4%) were pregnant at 300 DIM than cows with VD 1/2 (76.5%), VD 3 (76.2%), or VD 4 (74.7%). Hazard of pregnancy by 300 DIM was smaller for VD 5 compared with VD 1/2, VD 3, or VD 4 cows. A greater proportion of VD 5 cows were removed from the herd within 300 DIM compared with other VD groups. There was 760 kg lesser milk production within 300 DIM for VD 5 compared with VD 2, VD 3, and VD 4, whereas VD 2, VD 3, and VD 4 had similar milk production. We did not detect an association between fever at diagnosis of VD 5 and reproductive performance or milk production. A greater proportion of VD 5 cows without fever were removed from the herd by 300 DIM compared with VD 5 cows with fever. Differences in productive and reproductive performance, and removal of the herd were restricted to fetid, watery, and reddish/brownish vaginal discharge, which was independent of fever.

Do newborn lambs with black and white hair-coats in an equatorial semi-arid environment maintain homeothermy?

We assessed newborn lambs from two hair-coat sheep breeds, the black Santa Ines (n = 29) and white Dorper (n = 26), to determine how they behaviourally and physiologically respond to the prevailing thermal conditions in an equatorial semi-arid environment. Measurements of hair-coat surface temperature, rectal temperature and the lambs' exposure to sun were recorded across the first 24 h of life every hour, after the lambs had received colostrum. Lambs and ewes were kept in a lambing pen and could freely move between a shaded area or be exposed to sun. During the study period, the air temperature ranged between 20 ºC and 34 ºC. When exposed to sun, lambs and ewes could experience as much as 1200 W m-2 of solar irradiance. Santa Ines lambs exhibited higher (highest density interval at 95%, HDI) hair-coat surface temperatures than did Dorper lambs. Overall, both Santa Ines and Dorper lambs sustained homeothermy, with a mean rectal temperature ranging from 38.7 ºC to 39.1 ºC between night and daytime phase, and a mean amplitude of ~ 0.8 ºC. Nevertheless, from 10:00 to 15:00, some lambs were found to be moderately hyperthermic. Five Santa Ines and three Dorper lambs had rectal temperatures above 40 ºC, and one Santa Ines lamb, while exposed to sun, had a rectal temperature of 41.3 ºC. Over this time period, lambs were more likely to move to shade (HDI at 95%). From 00:00 to 06:00, despite the air temperature being lower than the hair-coat surface, favouring high rates of sensible heat loss to the environment, no lamb exhibited signs of hypothermia (rectal temperature < 37.5 ºC). In conclusion, haired newborn lambs coped well with high levels of radiant heat during the daytime and lower temperatures at night. However, providing access to shade during the daytime is important to improve the welfare of newborn lambs delivered in equatorial semi-arid regions.

The role of microglia in 67NR mammary tumor-induced suppression of brain responses to immune challenges in female mice.

It is poorly understood how solid peripheral tumors affect brain neuroimmune responses despite the various brain-mediated side effects and higher rates of infection reported in cancer patients. We hypothesized that chronic low-grade peripheral tumor-induced inflammation conditions microglia to drive suppression of neuroinflammatory responses to a subsequent peripheral immune challenge. Here, Balb/c murine mammary tumors attenuated the microglial inflammatory gene expression responses to lipopolysaccharide (LPS) and live Escherichia coli (E. coli) challenges and the fatigue response to an E. coli infection. In contrast, the inflammatory gene expression in response to LPS or a toll-like receptor 2 agonist of Percoll-enriched primary microglia cultures was comparable between tumor-bearing and -free mice, as were the neuroinflammatory and sickness behavioral responses to an intracerebroventricular interleukin (IL)-1ß injection. These data led to the hypothesis that Balb/c mammary tumors blunt the neuroinflammatory responses to an immune challenge via a mechanism involving tumor suppression of the peripheral humoral response. Balb/c mammary tumors modestly attenuated select circulating cytokine responses to LPS and E. coli challenges. Further, a second mammary tumor/mouse strain model (E0771 tumors in C57Bl/6 mice) displayed mildly elevated inflammatory responses to an immune challenge. Taken together, these data indicate that tumor-induced suppression of neuroinflammation and sickness behaviors may be driven by a blunted microglial phenotype, partly because of an attenuated peripheral signal to the brain, which may contribute to infection responses and behavioral side effects reported in cancer patients. Finally, these neuroimmune effects likely vary based on tumor type and/or host immune phenotype.

Kinetic modulation of bacterial hydrolases by microbial community structure in coastal waters.

In this study, we hypothesized that shifts in the kinetic parameters of extracellular hydrolytic enzymes may occur as a consequence of seasonal environmental disturbances and would reflect the level of adaptation of the bacterial community to the organic matter of the ecosystem. We measured the activities of enzymes that play a key role in the bacterial growth (leucine aminopeptidase, ß- and α-glucosidases) in surface coastal waters of the Eastern Cantabrian Sea and determined their kinetic parameters by computing kinetic models of distinct complexity. Our results revealed the existence of two clearly distinct enzymatic systems operating at different substrate concentrations: a high-affinity system prevailing at low substrate concentrations and a low-affinity system characteristic of high substrate concentrations. These findings could be the result of distinct functional bacterial assemblages growing concurrently under sharp gradients of high-molecular-weight compounds. We constructed an ecological network based on contemporaneous and time-delayed correlations to explore the associations between the kinetic parameters and the environmental variables. The analysis revealed that the recurring phytoplankton blooms registered throughout the seasonal cycle trigger the wax and wane of those members of the bacterial community able to synthesize and secrete specific enzymes.

Efficacy and safety of dolutegravir/rilpivirine in real-world clinical practice. GeSIDA study 1119.

INTRODUCTION: Dolutegravir/rilpivirine (DTG/RPV) is an effective antiretroviral (ART) regimen endorsed by clinical trials as a switch therapy. The aim of our study was to analyse the efficacy and safety of DTG/RPV in real-world clinical practice. METHODS: Observational, multicentre study of patients who started DTG/RPV. Efficacy, adverse events and metabolic changes at 48 weeks were analysed. RESULTS: A total of 348 patients were included; median time of HIV infection was 21.1 years, 33.7% were AIDS cases; median nadir CD4 was 160 cells/µL; 90.5% had received ≥3 lines of ART and 179 (53.8%) had prior virological failure. Convenience (43.5%), toxicity/intolerance (28.4%) and interactions (17.0%) were the main reasons for starting DTG/RPV. Previous regimens were protease inhibitors (PI) (31.6%), non-nucleoside reverse transcriptase inhibitors (NNRTI) (20.4%) and integrase strand transfer inhibitors (INSTI) (14.9%). Efficacy (HIV-RNA <50 copies/mL) at 48 weeks was 89.7% (95% CI 86.1-92.6) by intention-to-treat (ITT) and 94.2% (95% CI 91.3-96.4) by on treatment (OT); 10 patients (3.1%) were not suppressed (3 had abandoned ART). There was a mean decrease in triglycerides, total cholesterol, low-density lipoprotein-cholesterol, glutamic-pyruvic transaminase (GPT), gamma-glutamyl transferase (GGT) and alkaline phosphatase; creatinine increased with a decrease in glomerular filtration rate. CONCLUSIONS: This study confirms the effectiveness, tolerability and safety of DTG/RPV in real-world clinical practice in a different population from clinical trials, with many years of infection, low CD4 nadir, several previous treatment lines, more than half with virological failures, and one-third diagnosed with AIDS. The switch to DTG/RPV was safe with few discontinuations due to adverse effects. Modifications of the lipid and liver profiles were favourable. There were no relevant changes in kidney function.

Structural differences between hypoxanthine phosphoribosyltransferase family members highlight opportunities for antiparasitic drug design in neglected diseases.

Approaches to identify novel druggable targets for treating neglected diseases include computational studies that predict possible interactions of drugs and their molecular targets. Hypoxanthine phosphoribosyltransferase (HPRT) plays a central role in the purine salvage pathway. This enzyme is essential for the survival of the protozoan parasite T. cruzi, the causal agent of Chagas disease, and other parasites related to neglected diseases. Here we found dissimilar functional behaviours between TcHPRT and the human homologue, HsHPRT, in the presence of substrate analogues that can lie in differences in their oligomeric assemblies and structural features. To shed light on this issue, we carried out a comparative structural analysis between both enzymes. Our results show that HsHPRT is considerably more resistant to controlled proteolysis than TcHPRT. Moreover, we observed a variation in the length of two key loops depending on the structural arrangement of each protein (groups D1T1 and D1T1'). Such variations might be involved in inter-subunit communication or influencing the oligomeric state. Besides, to understand the molecular basis that govern D1T1 and D1T1' folding groups, we explored the distribution of charges on the interaction surfaces of TcHPRT and HsHPRT, respectively. To know whether the rigidity degree bears effect on the active site, we studied the flexibility of both proteins. The analysis performed here illuminates the underlying reasons and significance behind each protein's preference for one or the other quaternary arrangement that can be exploited for therapeutic approaches.

Tobacco use in first-episode psychosis, a multinational EU-GEI study.

BACKGROUND: Tobacco is a highly prevalent substance of abuse in patients with psychosis. Previous studies have reported an association between tobacco use and schizophrenia. The aim of this study was to analyze the relationship between tobacco use and first-episode psychosis (FEP), age at onset of psychosis, and specific diagnosis of psychosis. METHODS: The sample consisted of 1105 FEP patients and 1355 controls from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We assessed substance use with the Tobacco and Alcohol Questionnaire and performed a series of regression analyses using case-control status, age of onset of psychosis, and diagnosis as outcomes and tobacco use and frequency of tobacco use as predictors. Analyses were adjusted for sociodemographic characteristics, alcohol, and cannabis use. RESULTS: After controlling for cannabis use, FEP patients were 2.6 times more likely to use tobacco [p ⩽ 0.001; adjusted odds ratio (AOR) 2.6; 95% confidence interval (CI) [2.1-3.2]] and 1.7 times more likely to smoke 20 or more cigarettes a day (p = 0.003; AOR 1.7; 95% CI [1.2-2.4]) than controls. Tobacco use was associated with an earlier age at psychosis onset (ß = -2.3; p ⩽ 0.001; 95% CI [-3.7 to -0.9]) and was 1.3 times more frequent in FEP patients with a diagnosis of schizophrenia than in other diagnoses of psychosis (AOR 1.3; 95% CI [1.0-1.8]); however, these results were no longer significant after controlling for cannabis use. CONCLUSIONS: Tobacco and heavy-tobacco use are associated with increased odds of FEP. These findings further support the relevance of tobacco prevention in young populations.

Aggregation patterns of curcumin and piperine mixtures in different polar media.

This work reports a thorough molecular dynamics investigation on the aggregation patterns of curcumin and piperine in water, ethanol and a mixture of both solvents. The low solubility of curcumin in water results in a rapid formation of very stable dimers for both keto and enol tautomers. In agreement with a higher solubility, piperine molecules move closer and farther apart several times during the simulation, which indicates the formation of a less stable dimer in water. In contrast, both curcumin and piperine are soluble in ethanol and, thus, dimers can hardly be formed in this media. In comparison with a pure-water solvent, a 30 : 70 mixture of ethanol and water significantly reduces the probability of formation of most dimers of curcumin and piperine molecules. The simulations show that larger clusters may be complex structures, but the formation of stacks (in the case of piperine and enol tautomer of curcumin) and cages (when the keto tautomer of curcumin is involved) are not rare. Furthermore, it is shown that each single molecule presents a certain degree of mobility in the cluster, especially on the surface, but without leading to dissociation.

Rumen-protected choline reduces hepatic lipidosis by increasing hepatic triacylglycerol-rich lipoprotein secretion in dairy cows.

Objectives were to determine the effects of supplementing rumen-protected choline (RPC) on hepatic composition and secretion of triacylglycerol-rich lipoprotein when cows were subjected to feed restriction to develop fatty liver. It was hypothesized that RPC reduces hepatic triacylglycerol by enhancing secretion of hepatic lipoprotein. Pregnant, nonlactating parous Holstein cows (n = 33) at mean (± standard deviation) 234 ± 2.2 d of gestation were blocked by body condition (3.79 ± 0.49) and assigned to receive 0 g/d (CON), 25.8 g/d choline ion from a RPC product containing 28.8% choline chloride (CC; treatment L25.8), or 25.8 g/d of choline ion from a RPC product containing 60.0% CC (H25.8). Cows were fed for ad libitum intake for the first 5 d and restricted to 41% of the net energy for lactation required for maintenance and pregnancy from d 6 to 13. Intake of metabolizable methionine was maintained at 18 g/d during feed restriction by supplying rumen-protected methionine. Hepatic tissue was sampled on d 6 and 13 and analyzed for triacylglycerol and glycogen, and mRNA expression of hepatic tissue was investigated. On d 14, cows were not fed and received a 10% solution of tyloxapol intravenously at 120 mg/kg of body weight to block hydrolysis of triacylglycerols in very low density lipoprotein (VLDL). Blood was sampled sequentially for 720 min and analyzed for concentration of triacylglycerol and total cholesterol. Lymph was sampled 6 h after tyloxapol infusion, and analyzed for concentrations of fatty acids, ß-hydroxybutyrate, glucose, triacylglycerol, and total cholesterol. A sample of serum collected at 720 min after tyloxapol was assayed for the metabolome composition. The area under the curve (AUC) of serum triacylglycerol, VLDL cholesterol, and total cholesterol were calculated. Orthogonal contrasts evaluated the effect of supplementing RPC (CON vs. [1/2 L25.8 + 1/2 H25.8]) and source of RPC (L25.8 vs. H25.8). Least squares means and standard errors of the means are presented in sequence as CON, L25.8, H25.8. During feed restriction, supplementation of RPC reduced hepatic triacylglycerol (9.0 vs. 4.1 vs. 4.5 ± 0.6%) and increased glycogen contents (1.9 vs. 3.5 vs. 4.1 ± 0.2%). Similarly, supplementation of RPC increased the expression of transcripts involved in the synthesis and assembly of lipoproteins (MTTP), cellular autophagy (ATG3), and inflammation (TNFA), and reduced the expression of transcripts associated with mitochondrial oxidation of fatty acids (HADHA, MLYCD) and stabilization of lipid droplets (PLIN2). After infusion of tyloxapol, RPC increased the AUC for serum triacylglycerol (21,741 vs. 32,323 vs. 28,699 ± 3,706 mg/dL × min) and VLDL cholesterol (4,348 vs. 6,465 vs. 5,740 ± 741 mg/dL × min) but tended to reduce the concentrations of triacylglycerol in lymph (16.7 vs. 13.8 vs. 11.9 ± 1.9 mg/dL). Feeding RPC tended to increase the concentrations of 89 metabolites in serum, after adjusting for false discovery, including 3 acylcarnitines, 1 AA-related metabolite, 11 bile acids, 1 ceramide, 6 diacylglycerols, 2 dihydroceramides, 1 glycerophospholipid, and 64 triacylglycerols compared with CON. Feeding 25.8 g/d of choline ion as RPC mediated increased hepatic triacylglycerol secretion to promote lipotropic effects that reduced hepatic lipidosis in dairy cows.