Neurons of Macaque Frontal Eye Field Signal Reward-Related Surprise.

The frontal eye field (FEF) plays a well-established role in the control of visual attention. The strength of an FEF neuron's response to a visual stimulus presented in its receptive field is enhanced if the stimulus captures spatial attention by virtue of its salience. A stimulus can be rendered salient by cognitive factors as well as by physical attributes. These include surprise. The aim of the present experiment was to determine whether surprise-induced salience would result in enhanced visual response strength in the FEF. Toward this end, we monitored neuronal activity in two male monkeys while presenting first a visual cue predicting with high probability that the reward delivered at the end of the trial would be good or bad (large or small) and then a visual cue announcing the size of the impending reward with certainty. The second cue usually confirmed but occasionally violated the expectation set up by the first cue. Neurons responded more strongly to the second cue when it violated than when it confirmed expectation. The increase in firing rate was accompanied by a decrease in spike-count correlation as expected from capture of attention. Although both good surprise and bad surprise induced enhanced firing, the effects appeared to arise from distinct mechanisms as indicated by the fact that the bad-surprise signal appeared at a longer latency than the good-surprise signal, and by the fact that the strength of the two signals varied independently across neurons.Significance Statement Neurons in the macaque frontal eye field (FEF) respond strongly to cues predicting rewards. Their firing might be related to the representation of value or to the capture of attention. We set out to resolve this issue by monitoring neuronal responses to cues conveying surprising information about upcoming rewards. We find that surprising cues elicit enhanced responses regardless of whether the surprise is good (more reward than expected) or bad (less reward than expected). These findings, which constitute the first evidence for surprise-driven activity in the FEF, are most harmonious with an interpretation based on capture of attention.

TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells.

Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

Discussion of sound propagation through the turbulent Martian atmosphere and implications for inference of turbulence spectra.

Chide et al. [J. Acoust. Soc. Am. 155, 420-435 (2024)] provide a first attempt to infer the spectrum of temperature fluctuations on Mars from experimental data on the variances of travel-time and log-amplitude fluctuations recorded by the microphone on board the Perseverance rover. However, the theoretical formulations that were used to interpret the travel-time data have limitations. In addition to explaining those issues, this article also outlines approaches for predicting statistical characteristics of acoustic signals in the Martian atmosphere. In particular, the experimentally observed dependence of the travel-time variance on the propagation range can be attributed to ground-blocking of buoyantly produced turbulent velocity fluctuations and the non-Markov character of phase fluctuations.

A-to-I RNA Editing and Hematopoiesis.

Adenosine to inosine (A-to-I) RNA editing plays essential roles in modulating normal development and homeostasis. This process is catalyzed by Adenosine Deaminase Acting on RNA (ADAR) family proteins. The most well-understood biological processes modulated by A-to-I editing are innate immunity and neurological development, attributed to ADAR1 and ADAR2 respectively. A-to-I editing by ADAR1 is also critical in regulating hematopoiesis. This review will focus on the role of A-to-I RNA editing and ADAR enzymes, particularly ADAR1, during normal hematopoiesis in humans and mice. Furthermore, we will discuss Adar1 mouse models that have been developed to understand the contribution of ADAR1 to hematopoiesis and its role in innate immune pathways.

Basal forebrain-lateral habenula inputs and control of impulsive behavior.

Deficits in impulse control are observed in several neurocognitive disorders, including attention deficit hyperactivity (ADHD), substance use disorders (SUDs), and those following traumatic brain injury (TBI). Understanding brain circuits and mechanisms contributing to impulsive behavior may aid in identifying therapeutic interventions. We previously reported that intact lateral habenula (LHb) function is necessary to limit impulsivity defined by impaired response inhibition in rats. Here, we examine the involvement of a synaptic input to the LHb on response inhibition using cellular, circuit, and behavioral approaches. Retrograde fluorogold tracing identified basal forebrain (BF) inputs to LHb, primarily arising from ventral pallidum and nucleus accumbens shell (VP/NAcs). Glutamic acid decarboxylase and cannabinoid CB1 receptor (CB1R) mRNAs colocalized with fluorogold, suggesting a cannabinoid modulated GABAergic pathway. Optogenetic activation of these axons strongly inhibited LHb neuron action potentials and GABA release was tonically suppressed by an endogenous cannabinoid in vitro. Behavioral experiments showed that response inhibition during signaled reward omission was impaired when VP/NAcs inputs to LHb were optogenetically stimulated, whereas inhibition of this pathway did not alter LHb control of impulsivity. Systemic injection with the psychotropic phytocannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), also increased impulsivity in male, and not female rats, and this was blocked by LHb CB1R antagonism. However, as optogenetic VP/NAcs pathway inhibition did not alter impulse control, we conclude that the pro-impulsive effects of Δ9-THC likely do not occur via inhibition of this afferent. These results identify an inhibitory LHb afferent that is controlled by CB1Rs that can regulate impulsive behavior.

Effects of rate of body weight gain during the first trimester of gestation on beef heifer and offspring performance, concentrations of hormones and metabolites, and response to vaccination.

Our study objectives were to evaluate the effects of divergent rates of body weight (BW) gain during early gestation in beef heifers on F0 performance, metabolic and endocrine status, colostrum immunoglobulins, and subsequent F1 calf characteristics, growth performance, concentrations of hormones and metabolites, and response to vaccination. Angus-based heifers (n = 100; BW = 369 ±â€…2.5 kg) were adapted to individual feeding for 14 d and bred using artificial insemination with female-sexed semen. Heifers were ranked by BW and assigned to either a basal diet targeting 0.28 kg/d gain (low [LG], n = 50) or the basal diet plus an energy/protein supplement targeting 0.79 kg/d gain (moderate gain [MG], n = 50) until day 84 of gestation. Dam BW and blood samples were collected at 6 time points during gestation; body composition was evaluated on days -10 and 84; and fetal measurements were taken on days 42, 63, and 84. At calving (LG, n = 23; MG, n = 23), dam and calf BW were recorded; and colostrum, calf body measurements, and blood samples were collected. Cow-calf pairs were managed on a common diet from calving to weaning, followed by a common postnatal development period for all F1 female offspring. Growth performance, hormone and metabolite profiles, feeding behavior, and reproductive performance were assessed from birth to prebreeding in F1 heifers. Offspring were vaccinated against respiratory disease and bovine viral diarrhea pathogens on days 62.3 ±â€…4.13 and 220.3 ±â€…4.13 postcalving. By design, MG dams were heavier (P < 0.0001) than LG on day 84, and the BW advantage persisted until subsequent weaning of F1 calves. Concentrations of serum IGF-1 and glucose were increased throughout gestation (P < 0.001) in MG dams, whereas concentrations of NEFA were decreased (P < 0.001) in LG dams. Calves from MG dams were 2.14 kg heavier (P = 0.03) and had larger chest circumference (P = 0.04) at birth compared with LG cohorts. Heifers from MG dams continued to have greater (P ≤ 0.03) BW gain and feed efficiency during the development period, but no differences were observed (P ≥ 0.13) in body composition, concentrations of hormones and metabolites, feeding behavior, puberty attainment, and response to vaccination in F1 offspring. Hence, early gestation rate of gain impacted BW and concentrations of glucose and IGF-1 throughout gestation in the F0 dam, resulting in altered F1 calf BW and measurements at birth and increased gain and efficiency during the development period.

Generally, beef heifers are managed on grazing pastures during early gestation, which are subject to fluctuations in forage quantity and quality. Variations in the nutrients available to the dam can impact the developing offspring during early gestation. Providing energy/protein supplements to grazing cattle is a method to ensure nutrient requirements are being met and to enhance the rate of gain. This study modeled the effects of pasture supplementation in beef heifers during early gestation to determine whether 2 rates of body weight (BW) gain alter maternal body composition and concentrations of hormones and metabolites, as well as changes to postnatal characteristics of the subsequent F1 generation heifer calves. The rate of gain affected the heifer's BW, body composition, and concentrations of key metabolites and hormones, which likely altered the nutritional environment experienced by the fetus. Subsequently, F1 offspring from supplemented dams had greater morphometric characteristics at birth and had greater BW gain, feed efficiency, and eating rate during the postweaning development period. However, body composition, concentrations of hormones and metabolites, other feeding behaviors, puberty attainment, and response to vaccination of offspring were not affected. Further research is warranted to investigate how the early gestational rate of BW gain impacts key metabolic organs and mechanisms involved in transferring programming outcomes to subsequent generations.

How is tailored implementation undertaken using a self-guided toolkit? Qualitative study of the ItFits-toolkit in the ImpleMentAll project.

BACKGROUND: The process of tailored implementation is ill-defined and under-explored. The ItFits-toolkit was developed and subsequently tested as a self-guided online platform to facilitate implementation of tailored strategies for internet-based cognitive behavioural therapy (iCBT) services. In ImpleMentAll, ItFits-toolkit had a small but positive effect on the primary outcome of iCBT normalisation. This paper investigates, from a qualitative perspective, how implementation teams developed and undertook tailored implementation using the toolkit within the trial. METHODS: Implementation teams in thirteen sites from nine countries (Europe and Australia) used the ItFits-toolkit for six months minimum, consistent with the trial protocol. A qualitative process evaluation was conducted. Descriptive data regarding goals, barriers, strategies, and implementation plans collected within the toolkit informed qualitative data collection in real time. Qualitative data included remote longitudinal interviews (n = 55) with implementation team members (n = 30) and observations of support calls (n = 19) with study sites. Qualitative data were analysed thematically, using a team-based approach. RESULTS: Implementation teams developed and executed tailored implementation projects across all steps in the toolkit process. Working in a structured way but with room for flexibility, decisions were shaped by team members' ideas and goals, iterative stakeholder engagement, internal and external influences, and the context of the ImpleMentAll project. Although teams reported some positive impacts of their projects, 'time', both for undertaking the work, and for seeing project impacts, was described as a key factor in decisions about implementation strategies and assessments of success. CONCLUSION: This study responds directly to McHugh et al.'s (2022) call for empirical description of what implementation tailoring looks like in action, in service settings. Self-guided facilitation of tailored implementation enables implementers in service settings to undertake tailoring within their organisations. Implementation tailoring takes considerable time and involves detailed work but can be supported through the provision of implementation science informed guidance and materials, iterative and ongoing stakeholder engagement, and working reflectively in response to external influencing factors. Directions for advancement of tailored implementation are suggested.

One-carbon metabolite supplementation increases vitamin B12, folate, and methionine cycle metabolites in beef heifers and fetuses in an energy dependent manner at day 63 of gestation.

One-carbon metabolites (OCM) are metabolites and cofactors which include folate, vitamin B12, methionine, and choline that support methylation reactions. The objectives of this study were to investigate the effects of moderate changes in maternal body weight gain in combination with OCM supplementation during the first 63 d of gestation in beef cattle on (1) B12 and folate concentrations in maternal serum (2) folate cycle intermediates in maternal and fetal liver, allantoic fluid (ALF), and amniotic fluid (AMF) and (3) metabolites involved in one-carbon metabolism and related metabolic pathways in maternal and fetal liver. Heifers were either intake restricted (RES) and fed to lose 0.23 kg/d, or fed to gain 0.60 kg/d (CON). Supplemented (+ OCM) heifers were given B12 and folate injections weekly and fed rumen-protected methionine and choline daily, while non-supplemented (-OCM) heifers were given weekly saline injections. These two treatments were combined in a 2 × 2 factorial arrangement resulting in 4 treatments: CON-OCM, CON + OCM, RES-OCM, and RES + OCM. Samples of maternal serum, maternal and fetal liver, ALF, and AMF were collected at slaughter on day 63 of gestation. Restricted maternal nutrition most notably increased (./ ≤ 0.05) the concentration of vitamin B12 in maternal serum, 5,10-methylenetetrahydrofolate and 5,10-methenyltetrahydrofolate in maternal liver, and cystathionine in the fetal liver; conversely, maternal restriction decreased (P = 0.05) 5,10-methylenetetrahydrofolate concentration in fetal liver. Supplementing OCM increased (P ≤ 0.05) the concentrations of maternal serum B12, folate, and folate intermediates, ALF and AMF 5-methyltetrahydrofolate concentration, and altered (P ≤ 0.02) other maternal liver intermediates including S-adenosylmethionine, dimethylglycine, cystathionine Glutathione reduced, glutathione oxidized, taurine, serine, sarcosine, and pyridoxine. These data demonstrate that OCM supplementation was effective at increasing maternal OCM status. Furthermore, these data are similar to previously published literature where restricted maternal nutrition also affected maternal OCM status. Altering OCM status in both the dam and fetus could impact fetal developmental outcomes and production efficiencies. Lastly, these data demonstrate that fetal metabolite abundance is highly regulated, although the changes required to maintain homeostasis may program altered metabolism postnatally.

Maternal stresses that occur during pregnancy, such as restricted nutrition, can impact the developmental outcomes of the offspring in a process known as developmental programming. This programming can occur through epigenetics, which involves changes in fetal gene expression and can occur through the addition of methyl groups to DNA. These changes regulate gene transcription in the offspring and can alter offspring health, efficiency, and life-long outcomes. One-carbon metabolites (OCM), which are nutrients like the amino acid methionine and the vitamins B12, folate, and choline, act as intermediates or cofactors for the donation of methyl groups to DNA. This study investigated the effects of differing maternal rates of gain along with OCM supplementation during early gestation on OCM and related metabolite concentrations in the dam and fetus. We found that supplementing OCM to beef heifers increased maternal OCM and related metabolite concentrations and fetal fluid OCM concentrations. We also found that low maternal gain increased maternal serum and liver OCM concentrations. We can conclude from these findings that both maternal rate of gain and OCM supplementation can impact maternal OCM concentrations at day 63 of gestation and further research is needed to see if those maternal impacts will affect the developing fetus or calf later in its life.

Differing planes of nutrition alter serum and histotroph amino acid composition in nonpregnant, multiparous beef cows on day 3 of the estrous cycle.

Endometrial-derived uterine histotroph is a critical component of nutrient supply to a growing conceptus throughout gestation; however, the effect of nutritional plane on histotroph nutrient composition remains unknown in multiparous cows. We hypothesized that differing planes of nutrition would alter histotroph and serum nutrient composition in beef cattle. Thus, we evaluated serum and histotroph amino acid and glucose composition, and serum non-esterified fatty acids (NEFA) and blood urea nitrogen (BUN) in cows individually fed to maintain body weight (BW; 0 kd/d, n = 9; CON) compared with those losing moderate BW (-0.7 kg/d, n = 9; NEG). After 49 d of differing nutritional planes, cows were subjected to the 7-d CoSynch + controlled internal drug release device estrus synchronization protocol and then slaughtered on day 62. Blood serum (days 0 and 62) and uterine histotroph [day 62; from uterine horns ipsilateral and contralateral to the corpus luteum (CL)] were collected and analyzed for concentrations of amino acids, glucose, and NEFA. Performance characteristics, body composition via ultrasound (days 0 and 62), and carcass characteristics were collected. Body condition score, change in BW, average daily gain, dry matter intake, and gain:feed were decreased (P ≤ 0.05) in NEG vs. CON cows. There were no differences in body composition or carcass characteristics, except an increase (P ≤ 0.05) in dressing percentage in NEG cows due to differences in gut fill, consistent with study design. Serum NEFA increased (P ≤ 0.05) in the NEG group, but there were no differences between NEG vs. CON in glucose or BUN. Serum histidine increased (P ≤ 0.05) and alanine, isoleucine, and tryptophan decreased (P ≤ 0.05) in NEG vs. CON cows. Compared with that of the uterine horn ipsilateral to the CL, histotroph from the uterine horn contralateral to the CL had increased (P ≤ 0.05) isoleucine, asparagine, and proline concentrations in NEG cows, and decreased (P ≤ 0.05) tryptophan as a proportion of essential and total amino acids. There were no differences in glucose concentrations of histotroph contralateral or ipsilateral to the CL. Cow nutritional plane does alter serum and histotroph amino acid composition, although the presence of an embryo may be necessary to fully elucidate these changes. Differences in serum and histotroph tryptophan should be given consideration in future studies due to its importance as an essential amino acid in protein synthesis and bioactive affects.

Amino acids are important in protein synthesis and bioactive affects. Maternal diet could impact histotroph amino acid composition which serves as a nutrient supply to the conceptus throughout pregnancy and is especially critical during early pregnancy, before the placenta is fully functional. Cows were subjected to their diets for 62 d, resulting in decreased body condition, average daily gain, dry matter intake, G:F, and a greater change in body weight (BW) among moderate loss cows. These data demonstrate our model for moderate BW loss was successful. Moderate BW loss cows exhibited alterations in serum and histotroph amino acid composition in the uterine horn contralateral to the corpus luteum (CL). However, in the present study, histotroph amino acid alterations were in the uterine horn contralateral to the CL, which would be opposite of the developing conceptus. Nevertheless, because the 2 uterine horns communicate via the common uterine body, the pre-implantation conceptus should have access to the histotroph from the contralateral uterine horn. Thus, future studies are needed to fully elucidate effects of nutritional plane on histotroph nutrient composition, and its potential impact on pregnancy.

Divergent planes of nutrition in mature rams influences body composition, hormone and metabolite concentrations, and offspring birth measurements, but not semen characteristics or offspring growth.

Objectives of this experiment were to characterize the effects of ram plane of nutrition on body composition, concentrations of hormones and metabolites, sperm characteristics, and offspring outcomes. Mature Rambouillet rams (n = 24, BW = 82.9 ±â€…2.63 kg) were individually housed and randomly assigned to either a positive (POS; n = 8), maintenance (MAINT; n = 8), or negative (NEG; n = 8) plane of nutrition for an 84-day feeding period. Rams were fed a common diet, with daily feed allocations adjusted weekly based on body weight (BW) to achieve the targeted weight gain or loss (approximately 12% of initial BW). On 0, 28, 56, and 84-d, body condition score (BCS) and scrotal circumference (SC) were recorded, and blood and semen were collected. Following the feeding period, rams were placed in pens with 10 ewes each for a 28-d breeding period. Ewes were managed similarly throughout gestation and body weight and measurements were recorded at birth and weaning. Data were analyzed as repeated measures in time where appropriate with the mixed procedure of SAS, and individual ram was the experimental unit for all analysis. Ram BW was influenced by a treatment × day interaction (P < 0.001), with POS (0.12 ±â€…0.01 kg) having greater daily weight change than MAINT (0.1 ±â€…0.01 kg), which was greater than NEG (-0.12 ±â€…0.01 kg). Ram BCS and SC were influenced by treatment × day interactions (P ≤ 0.01), being similar on day 0 but POS being greater than NEG by day 56. Concentrations of triiodothyronine (T3) and T3:T4 ratio exhibited treatment × day interactions (P ≤ 0.02), as POS had greater values than NEG by day 84 (P ≤ 0.02). Concentration of insulin-like growth factor-1 was greater in POS than MAINT and NEG (P ≤ 0.02), and non-esterified fatty acids and thyroxine (T4) were influenced by a day effect (P ≤ 0.01), but testosterone was unaffected (P ≥ 0.09). Minimal differences in semen volume, sperm concentration, motility, or morphology were observed among treatments (P ≥ 0.31). A similar proportion of ewes bred by rams in the respective treatments lambed and weaned lambs (P ≥ 0.54). Birth weight, chest circumference, and shoulder-hip length were greater (P ≤ 0.05) in NEG lambs compared with POS and MAINT; however, no differences were detected in weaning weight and weaning body measurements (P ≥ 0.40). Findings suggest paternal nutrition during the period of sperm development may influence offspring outcomes, potentially as a result of in-utero programming of paternal origin.

This study was conducted to evaluate whether ram nutrition during the spermatogenesis impacts their body composition, concentrations of circulating hormones and metabolites, semen characteristics, fertility, and subsequent offspring growth and development. Rams were managed on treatments to gain, lose, or maintain body weight over an 84-day period. The changes in ram body weight that were imposed by our treatments resulted in changes in body condition score, scrotal circumference, and concentrations of several metabolic hormones, including thyroid hormones and insulin-like growth factor-1. However, no differences in sperm concentration or motility were observed. After the 84-d feeding period, rams were placed with ewes for a 28-d breeding period and ewes were monitored throughout gestation, lambing, and until weaning of the resulting lambs. Although no differences in ewe pregnancy rates were observed after the breeding period, lamb birth weight and body measurements were greater in rams that lost weight during spermatogenesis. Thereafter, body weight and growth performance of offspring were similar among sire treatments, but continued evaluation of offspring throughout the postnatal period is necessary. These findings indicate that paternal nutrition during spermatogenesis can impact offspring outcomes, potentially through epigenetic alterations to the sperm and subsequent in-utero programming of paternal origin.

Water-Soluble and Freezable Aluminum Salt Vaccine Adjuvant.

Particulate aluminum salts have long occupied a central place worldwide as inexpensive immunostimulatory adjuvants that enable induction of protective immunity for vaccines. Despite their huge benefits and safety, the particulate structures of aluminum salts require transportation and storage at temperatures between 2 °C and 8 °C, and they all have exquisite sensitivity to damage caused by freezing. Here, we propose to solve the critical freezing vulnerability of particulate aluminum salt adjuvants by introducing soluble aluminum salts as adjuvants. The solubility properties of fresh and frozen aluminum chloride and aluminum triacetate, each buffered optimally with sodium acetate, were demonstrated with visual observations and with UV-vis scattering analyses. Two proteins, A244 gp120 and CRM197, adjuvanted either with soluble aluminum chloride or soluble aluminum triacetate, each buffered by sodium acetate at pH 6.5-7.4, elicited murine immune responses that were equivalent to those obtained with Alhydrogel®, a commercial particulate aluminum hydroxide adjuvant. The discovery of the adjuvanticity of soluble aluminum salts might require the creation of a new adjuvant mechanism for aluminum salts in general. However, soluble aluminum salts might provide a practical substitute for particulate aluminum salts as vaccine adjuvants, thereby avoiding the risk of inactivation of vaccines due to accidental freezing of aluminum salt particles.

lncRNA-gene network analysis reveals the effects of early maternal nutrition on mineral homeostasis and energy metabolism in the fetal liver transcriptome of beef heifers.

Maternal nutrition during pregnancy influences fetal development; however, the regulatory markers of fetal programming across different gestational phases remain underexplored in livestock models. Herein, we investigated the regulatory role of long non-coding RNAs (lncRNAs) on fetal liver gene expression, the impacts of maternal vitamin and mineral supplementation, and the rate of maternal body weight gain during the periconceptual period. To this end, crossbred Angus heifers (n=31) were randomly assigned to a 2×2 factorial design to evaluate the main effects of the rate of weight gain (low gain [LG, avg. daily gain of 0.28 kg/day] vs. moderate gain [MG, avg. daily gain of 0.79 kg/day]) and vitamins and minerals supplementation (VTM vs. NoVTM). On day 83±0.27 of gestation, fetuses were collected for morphometric measurements, and fetal liver was collected for transcriptomic and mineral analyses. The maternal diet significantly affected fetal liver development and mineral reserves. Using an RNA-Seq approach, we identified 320 unique differentially expressed genes (DEGs) across all six comparisons (FDR <0.05). Furthermore, lncRNAs were predicted through the FEELnc pipeline, revealing 99 unique differentially expressed lncRNAs (DELs). The over-represented pathways and biological processes (BPs) were associated with energy metabolism, Wnt signaling, CoA carboxylase activity, and fatty acid metabolism. The DEL-regulated BPs were associated with metal ion transport, pyrimidine metabolism, and classical energy metabolism-related glycolytic, gluconeogenic, and TCA cycle pathways. Our findings suggest that lncRNAs regulate mineral homeostasis- and energy metabolism-related gene networks in the fetal liver in response to early maternal nutrition.

Pharmacists' clinical decision making when responding to a self-medication request for a cough in a developing country.

BACKGROUND: Some studies have reported that community pharmacies in developing countries, including Indonesia, provided sub-optimal advice when handling patient's self-medication request for cough. The reasons behind such advice, therefore, need to be investigated. OBJECTIVES: To describe Indonesian pharmacists' clinical decision making when handling self-medication cases for a cough. METHODS: An open-ended questionnaire consisting of two cough clinical vignettes (case 1: cough due to asthma worsening and case 2: cough as a symptom of common cold) were developed. Pharmacists were interviewed to provide recommendations and reasons for their recommendations for these scenarios. Content analysis was used to analyse participants' statements for the two scenarios. The number of participants who provided appropriate recommendations and reasons were then counted. RESULTS: A total of 245 community pharmacists participated in the study. In the case of cough due to asthma worsening, recommending a product because the product was indicated to help with the symptoms was the most common recommendation and stated reason (40%). Appropriate recommendation (direct medical referral) with appropriate reasoning (indicating warning symptoms and/or making a symptom diagnosis) was provided by 25% participants. In the case of cough as a symptom of common cold, recommending products to help with the symptoms was also the most common recommendation and stated reason (53%). Appropriate recommendations (recommending product) with appropriate reasoning (providing product to treat the symptoms and/or indicating no warning symptoms and/or making a symptom diagnosis) was provided by 81% participants. CONCLUSION: The ability of Indonesian community pharmacists to provide appropriate recommendations for cough self-medication requests is dependent on whether triage is required. The inability of most community pharmacists to differentiate between major and minor conditions may lead to serious health implications for patients and therefore educational interventions should be undertaken to improve community pharmacists' differential diagnostic skills for triage.

Disrupted one-carbon metabolism in heifers negatively affects their health and physiology.

The objective of this study was to determine the dose-dependent response of one-carbon metabolite (OCM: methionine, choline, folate, and vitamin B12) supplementation on heifer dry matter intake on fixed gain, organ mass, hematology, cytokine concentration, pancreatic and jejunal enzyme activity, and muscle hydrogen peroxide production. Angus heifers (n = 30; body weight [BW] = 392.6 ±â€…12.6 kg) were individually fed and assigned to one of five treatments: 0XNEG: total mixed ration (TMR) and saline injections at days 0 and 7 of the estrous cycle, 0XPOS: TMR, rumen-protected methionine (MET) fed at 0.08% of the diet dry matter, rumen-protected choline (CHOL) fed at 60 g/d, and saline injections at days 0 and 7, 0.5X: TMR, MET, CHOL, 5-mg B12, and 80-mg folate injections at days 0 and 7, 1X: TMR, MET CHOL, 10-mg vitamin B12, and 160-mg folate at days 0 and 7, and 2X: TMR, MET, CHOL, 20-mg vitamin B12, and 320-mg folate at days 0 and 7. All heifers were estrus synchronized but not bred, and blood samples were collected on days 0, 7, and at slaughter (day 14) during which tissues were collected. By design, heifer ADG did not differ (P = 0.96). Spleen weight and uterine weight were affected cubically (P = 0.03) decreasing from 0XPOS to 0.5X. Ovarian weight decreased linearly (P < 0.01) with increasing folate and B12 injection. Hemoglobin and hematocrit percentage were decreased (P < 0.01) in the 0.5X treatment compared with all other treatments. Plasma glucose, histotroph protein, and pancreatic α-amylase were decreased (P ≤ 0.04) in the 0.5X treatment. Heifers on the 2X treatment had greater pancreatic α-amylase compared with 0XNEG and 0.5X treatment. Interleukin-6 in plasma tended (P = 0.08) to be greater in the 0XPOS heifers compared with all other treatments. Lastly, 0XPOS-treated heifers had reduced (P ≤ 0.07) hydrogen peroxide production in muscle compared with 0XNEG heifers. These data imply that while certain doses of OCM do not improve whole animal physiology, OCM supplementation doses that disrupt one-carbon metabolism, such as that of the 0.5X treatment, can induce a negative systemic response that results in negative effects in both the dam and the conceptus during early gestation. Therefore, it is necessary to simultaneously establish an optimal OCM dose that increases circulating concentrations for use by the dam and the conceptus, while avoiding potential negative side effects of a disruptive OCM, to evaluate the long-term impacts of OCM supplementation of offspring programming.

The feeding of one-carbon metabolites (including methionine and B vitamins) has been shown to improve fetal growth and milk production in species such as mice, sheep, and dairy cattle. Extending this to beef cattle around the time of breeding is a growing area of research. Our group previously determined that one-carbon metabolite supplementation to beef heifers altered the abundance of circulating methionine-folate cycle intermediates in a dose-dependent manner. Therefore, we aimed to determine a whole-body response to one-carbon metabolite supplementation in heifers by measuring the effects on specific physiological systems as well as a total systemic response. We determined that treatments that negatively altered the methionine-folate cycle yielded a fundamental negative whole-body response to supplementation.

Contribution of the seminal microbiome to paternal programming.

The field of Developmental Origins of Health and Disease has primarily focused on maternal programming of offspring health. However, emerging evidence suggests that paternal factors, including the seminal microbiome, could potentially play important roles in shaping the developmental trajectory and long-term offspring health outcomes. Historically, the microbes present in the semen were regarded as inherently pathogenic agents. However, this dogma has recently been challenged by the discovery of a diverse commensal microbial community within the semen of healthy males. In addition, recent studies suggest that the transmission of semen-associated microbes into the female reproductive tract during mating has potentials to not only influence female fertility and embryo development but could also contribute to paternal programming in the offspring. In this review, we summarize the current knowledge on the seminal microbiota in both humans and animals followed by discussing their potential involvement in paternal programming of offspring health. We also propose and discuss potential mechanisms through which paternal influences are transmitted to offspring via the seminal microbiome. Overall, this review provides insights into the seminal microbiome-based paternal programing, which will expand our understanding of the potential paternal programming mechanisms which are currently focused primarily on the epigenetic modifications, oxidative stresses, and cytokines.

Vitamin and mineral supplementation to beef heifers during gestation: impacts on morphometric measurements of the neonatal calf, vitamin and trace mineral status, blood metabolite and endocrine profiles, and calf organ characteristics at 30 h after birth.

To examine the effects of feeding a vitamin and mineral supplement to beef heifers throughout gestation on mineral status and hormone/endocrine profiles in the dam and calf, and morphometric characteristics and organ mass of the calf at 30 h after birth, Angus-based heifers (n = 72, 14 to 15 mo of age, initial body weight [BW] = 380.4 ±â€…50.56 kg) were estrus synchronized and artificially inseminated (AI) with female-sexed semen. Heifers were blocked by BW and randomly assigned to receive either a basal diet (CON; n = 36) or a basal diet plus a vitamin and mineral supplement (VTM; n = 36) via an individual feeding system beginning at breeding, with both diets targeting BW gains of 0.45 kg heifer-1·d-1. Heifers not pregnant after the first AI (CON, n = 19; VTM, n = 18) were rebred via AI 60 d after treatment initiation, and heifers gestating female fetuses (CON, n = 7; VTM, n = 7) received treatments throughout gestation and were experimental units for this study. Calves were separated from their dams and fed colostrum replacer within 2 h of birth and euthanized 30 h after the first feeding. Calf morphometrics were recorded, and tissues were weighed and sampled. Serum from the dam at calving and serum, liver, and muscle from the calf at 30 h were analyzed for concentrations of minerals. Serum from the dam and calf were analyzed for concentrations of leptin, vitamins A, D, and E, cortisol, growth hormone, and insulin-like growth factor 1. All response variables were analyzed using the MIXED procedure of SAS. Calf body morphometrics and BW of the dam at calving (P ≥ 0.32), calf organ weights (P ≥ 0.21), and calf ovarian follicle counts (P ≥ 0.13) were not affected by maternal treatment. Concentrations of Se and Co in calf serum and Se in calf liver were increased (P ≤ 0.02) in VTM. Serum concentrations of Co and vitamin A in the dam were greater (P ≤ 0.01) in supplemented compared with nonsupplemented dams, and serum concentrations of vitamin D were greater (P ≤ 0.0003) in supplemented dams and calves compared with the nonsupplemented cohort. Maternal supplementation supported vitamin and mineral status in the neonate, yet had no discernable impact on BW, organ mass, or circulating hormones/metabolites in the calf. Evaluating offspring at later postnatal time points is warranted to determine if prenatal vitamin and mineral supplementation affects performance, health, metabolism, and efficiency of energy utilization in key metabolic tissues in the calf.

Vitamins and minerals are essential for the reproduction, performance, skeletal support, and overall health of beef cattle. During pregnancy, vitamins and minerals are critical for proper fetal growth, development, and establishment of postnatal micronutrient reserves. The study objectives were to evaluate the impacts of vitamin and mineral supplementation to beef heifers throughout gestation on female offspring morphometric characteristics at birth, mineral status and blood metabolite/endocrine profiles of the dam and calf, histological evaluation of calf ovaries, and organ weights of the neonate at 30 h of age. We hypothesized that vitamin and mineral supplementation to the dam during pregnancy would increase calf size and organ masses, mineral status, and blood metabolite and hormone profiles. We observed no differences in calf body measurements, organ masses, and offspring ovarian reserve between calves from supplemented and nonsupplemented dams. However, Co, Se, and vitamin D status was increased in the supplemented dam and calf, and we propose that enhanced vitamin and mineral status at birth may support the underdeveloped immune system, growth performance, and overall health of the neonate in the postnatal period. Further research is warranted to investigate postnatal offspring health, performance, and efficiency of energy utilization in key metabolic tissues in the calf.

Influence of Maternal Nutrition and One-Carbon Metabolites Supplementation during Early Pregnancy on Bovine Fetal Small Intestine Vascularity and Cell Proliferation.

To investigate the effects of nutrient restriction and one-carbon metabolite (OCM) supplementation (folate, vitamin B12, methionine, and choline) on fetal small intestine weight, vascularity, and cell proliferation, 29 (n = 7 ± 1 per treatment) crossbred Angus beef heifers (436 ± 42 kg) were estrous synchronized and conceived by artificial insemination with female sexed semen from a single sire. Then, they were allotted randomly to one of four treatments in a 2 × 2 factorial arrangement with the main factors of nutritional plane [control (CON) vs. restricted feed intake (RES)] and OCM supplementation [without OCM (-OCM) or with OCM (+OCM)]. Heifers receiving the CON level of intake were fed to target an average daily gain of 0.45 kg/day, which would allow them to reach 80% of mature BW by calving. Heifers receiving the RES level of intake were fed to lose 0.23 kg/heifer daily, which mimics observed production responses in heifers that experience a diet and environment change during early gestation. Targeted heifer gain and OCM treatments were administered from d 0 to 63 of gestation, and then all heifers were fed a common diet targeting 0.45 kg/d gain until d 161 of gestation, when heifers were slaughtered, and fetal jejunum was collected. Gain had no effect (p = 0.17) on the fetal small intestinal weight. However, OCM treatments (p = 0.02) displayed less weight compared to the -OCM groups. Capillary area density was increased in fetal jejunal villi of RES - OCM (p = 0.02). Vascular endothelial growth factor receptor 2 (VEGFR2) positivity ratio tended to be greater (p = 0.08) in villi and was less in the crypts (p = 0.02) of the RES + OCM group. Cell proliferation decreased (p = 0.02) in villi and crypts of fetal jejunal tissue from heifers fed the RES + OCM treatment compared with all groups and CON - OCM, respectively. Spatial cell density increased in RES - OCM compared with CON + OCM (p = 0.05). Combined, these data show OCM supplementation can increase expression of VEGFR2 in jejunal villi, which will promote maintenance of the microvascular beds, while at the same time decreasing small intestine weight and crypt cell proliferation.

Development of an adaptation framework to implement a new professional pharmacy service (PPS) to a new environment.

The effective provision of professional pharmacy services is critical to support the delivery of primary health care. Structured frameworks and theoretical strategies are required to facilitate successful service implementation processes, outcomes and sustainability. This commentary discusses the considerations of what framework (adoption versus adaptation) would be suitable when implementing a new professional pharmacy service to a new environment. Utilizing Minor Ailments Services (MASs) as an exemplar as a professional pharmacy service case study, the research that underpinned these considerations enabled the development of a sequential, phased framework. There is the potential to utilize this framework for future evolving professional pharmacy services in the new setting.

Influence of Maternal Supplementation with Vitamins, Minerals, and (or) Protein/Energy on Placental Development and Angiogenic Factors in Beef Heifers during Pregnancy.

The effect of vitamins and minerals supplementation (VTM) and/or two rates of body weight gain (GAIN) on bovine placental vascular development and angiogenic factors gene expression were evaluated in two experiments: In Exp. 1, crossbred Angus heifers (n = 34) were assigned to VTM/NoVTM treatments at least 71 days before breeding to allow changes in the mineral status. At breeding, through artificial insemination (AI), heifers were assigned to low-gain (LG) 0.28 kg/d or moderate-gain (MG) 0.79 kg/d treatments, resulting in NoVTM-LG (Control; n = 8), NoVTM-MG (n = 8), VTM-LG (n = 9), and VTM-MG (n = 9) until day 83 of gestation; In Exp. 2, crossbred angus heifers (n = 28), were assigned to control (CON; n = 12), receiving a basal total mixed ration (TMR) or TMR + VTM (VTM; n = 16) from breeding until parturition. Placentomes from Exp. 1 and cotyledons (COT) from Exp. 2 were evaluated by immunohistochemistry for COT vascular density area. COTs from Exp. 1 were evaluated for angiogenic factor (ANGPT-1, ANGPT-2, eNOS2, eNOS3, FLT1, KDR, TEK, VEGFA) gene expression. In Exp. 1, COT vascularity was not affected by the interaction of VTM and GAIN (p = 0.67) or the main effects of VTM (p = 0.50) and GAIN (p = 0.55). Likewise, angiogenic factors were not differentially expressed between treatments (p < 0.05). In Exp. 2, COT vascularity was greater in VTM vs. CON (p = 0.07). In conclusion, there is a suggested later-stage influence of vitamin and mineral supplementation on placental vascularity, emphasizing the importance of supplementation beyond early pregnancy.

Climate Change and Children's Health: Building a Healthy Future for Every Child.

Observed changes in temperature, precipitation patterns, sea level, and extreme weather are destabilizing major determinants of human health. Children are at higher risk of climate-related health burdens than adults because of their unique behavior patterns; developing organ systems and physiology; greater exposure to air, food, and water contaminants per unit of body weight; and dependence on caregivers. Climate change harms children through numerous pathways, including air pollution, heat exposure, floods and hurricanes, food insecurity and nutrition, changing epidemiology of infections, and mental health harms. As the planet continues to warm, climate change's impacts will worsen, threatening to define the health and welfare of children at every stage of their lives. Children who already bear higher burden of disease because of living in low-wealth households and communities, lack of access to high quality education, and experiencing racism and other forms of unjust discrimination bear greater risk of suffering from climate change hazards. Climate change solutions, advanced through collaborative work of pediatricians, health systems, communities, corporations, and governments lead to immediate gains in child health and equity and build a foundation for generations of children to thrive. This technical report reviews the nature of climate change and its associated child health effects and supports the recommendations in the accompanying policy statement on climate change and children's health.