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There is emerging evidence that there are genetic modifiers of iron indices for HFE gene mutation carriers at risk of hereditary hemochromatosis. A random sample, stratified by HFE genotype, of 863 from a cohort of 31 192 people of northern European descent provided blood samples for genotyping of 476 single nucleotide polymorphisms (SNPs) in 44 genes involved in iron metabolism. Single SNP association testing, using linear regression models adjusted for sex, menopause and HFE genotype, was conducted for four continuously distributed outcomes: serum ferritin (log transformed), transferrin saturation, serum transferrin, and serum iron. The SNP rs884409 in CYBRD1 is a novel modifier specific to HFE C282Y homozygotes. Median unadjusted serum ferritin concentration decreased from 1194 μg/l ( N = 27) to 387 μg/l ( N = 16) for male C282Y homozygotes and from 357 μg/l ( N = 42) to 69 μg/l ( N = 12) for females, comparing those with no copies to those with one copy of rs884409. Functional testing of this CYBRD1 promoter polymorphism using a heterologous expression assay resulted in a 30% decrease in basal promoter activity relative to the common genotype ( P = 0·004). This putative genetic modifier of iron overload expression accounts for 11% (95% CI 0·4%, 22·6%) of the variance in serum ferritin levels of C282Y homozygotes. [ABSTRACT FROM AUTHOR]

Presents a study which described a modeling analysis of the geochemical evolution of a contaminated sandy aquifer at a uranium mill tailings site in the western United States. Site characteristics; Field sampling and analytical data; Speciation and solubility modeling.

Excess levels of circulating androgens during prenatal or peripubertal development are an important cause of polycystic ovary syndrome (PCOS), with the brain being a key target. Approximately half of the women diagnosed with PCOS also experience metabolic syndrome; common features including obesity, insulin resistance and hyperinsulinemia. Although a large amount of clinical and preclinical evidence has confirmed this relationship between androgens and the reproductive and metabolic features of PCOS, the mechanisms by which androgens cause this dysregulation are unknown. Neuron‐specific androgen receptor knockout alleviates some PCOS‐like features in a peripubertal dihydrotestosterone (DHT) mouse model, but the specific neuronal populations mediating these effects are undefined. A candidate population is the agouti‐related peptide (AgRP)‐expressing neurons, which are important for both reproductive and metabolic function. We used a well‐characterised peripubertal androgenized mouse model and Cre‐loxP transgenics to investigate whether deleting androgen receptors specifically from AgRP neurons can alleviate the induced reproductive and metabolic dysregulation. Androgen receptors were co‐expressed in 66% of AgRP neurons in control mice, but only in <2% of AgRP neurons in knockout mice. The number of AgRP neurons was not altered by the treatments. Only 20% of androgen receptor knockout mice showed rescue of DHT‐induced androgen‐induced anovulation and acyclicity. Furthermore, androgen receptor knockout did not rescue metabolic dysfunction (body weight, adiposity or glucose and insulin tolerance). While we cannot rule out developmental compensation in our model, these results suggest peripubertal androgen excess does not markedly influence Agrp expression and does not dysregulate reproductive and metabolic function through direct actions of androgens onto AgRP neurons. [ABSTRACT FROM AUTHOR]

Infertility associated with insulin resistance is characterised by abnormal hormone secretion by the hypothalamus, pituitary gland and gonads. These endocrine tissues can maintain insulin sensitivity even when tissues such as the muscle and liver become insulin‐resistant, resulting in excessive insulin stimulation as hyperinsulinaemia develops. Experiments conducted to determine the role of neuronal insulin signalling in fertility were unable to recapitulate early findings of hypogonadotrophic hypogonadism in mice lacking insulin receptors throughout the brain. Rather, it was eventually shown that astrocytes critically mediate the effects of insulin on puberty timing and adult reproductive function. However, specific roles for neurones and gonadotrophs have been revealed under conditions of hyperinsulinaemia and by ablation of insulin and leptin receptors. The collective picture is one of multiple insulin‐responsive inputs to gonadotrophin releasing hormone neurones, with astrocytes being the most important player. [ABSTRACT FROM AUTHOR]

Lawrie and Margaret had five children, and he is survived by Elizabeth - herself a distinguished hepatologist, Mark, Martine and Christa. GLO:EUW/01nov22:jgh16031-gra-0001.jpg PHOTO (COLOR): . gl More than "Mr. Iron", Lawrie Powell was a Foundation Stone of Asia-Pacific Gastroenterology and Liver disease. Remembering Lawrie Powell 1934-2022. [Extracted from the article]

Agouti‐related peptide (AgRP) neurons are thought to indirectly regulate the activity of hypothalamic gonadotrophin‐releasing hormone neurons which control fertility. AgRP neurons also drive caloric intake and are modulated by metabolically‐relevant hormones, providing a link to the hypothalamic–pituitary‐gonadal axis. In mice expressing Cre‐dependant designer receptors (DREADDs) in AgRP neurons, we activated or silenced these neurons in vivo using the synthetic ligand clozapine‐N‐oxide (CNO) to observe the effect of AgRP neuron activity on timing of puberty. To validate these animals, we chronically treated both stimulatory (hM3Dq) and inhibitory (hM4Di) DREADD × AgRP‐Cre mice with CNO, observing a pronounced increase and decrease of food intake, respectively, consistent with the known orexigenic effects of these neurons. RNAscope was performed to visually confirm the activation of AgRP neurons. Puberty onset was assessed in males and females. There was no effect on preputial separation in males or vaginal opening and first oestrus in females after CNO treatment from day 26 to 30 to chronically modulate AgRP neurons. Next, to determine whether the delay in puberty onset occurring in response to neonatal underfeeding could be overcome by inhibiting AgRP neuronal activity, mice were raised in large (neonatally underfed) or normal litter sizes. The delay in puberty from underfeeding was completely reversed in CNO‐treated AgRP‐hM4Di male mice. These data highlight the inhibitory role of AgRP neurons to delay puberty onset when undernutrition occurs during the neonatal period, at least in male mice. Trail registration number: JNE‐22‐0081‐OA.R2 [ABSTRACT FROM AUTHOR]

Chronic stress exerts multiple negative effects on the physiology and health of an individual. In the present study, we examined hypothalamic, pituitary and endocrine responses to 14 days of chronic variable stress (CVS) in male and female C57BL/6J mice. In both sexes, CVS induced a significant decrease in body weight and enhanced the acute corticosterone stress response, which was accompanied by a reduction in thymus weight only in females. However, single‐point blood measurements of basal prolactin, thyroid‐stimulating hormone, luteinising hormone, growth hormone and corticosterone levels taken at the end of the CVS were not different from those of controls. Similarly, pituitary mRNA expression of Fshb, Lhb, Prl and Gh was unchanged by CVS, although Pomc and Tsh were significantly elevated. Within the adrenal medulla, mRNA for Th, Vip and Gal were elevated following CVS. Avp transcript levels within the paraventricular nucleus of the hypothalamus were increased by CVS; however, levels of Gnrh1, Crh, Oxt,Sst, Trh, Ghrh, Th and Kiss1 remained unchanged. Oestrous cycles were lengthened slightly by CVS and ovarian histology revealed a reduction in the number of preovulatory follicles and corpora lutea. Taken together, these observations indicate that 14 days of CVS induces an up‐regulation of the neuroendocrine stress axis and creates a mild disruption of female reproductive function. However, the lack of changes in other neuroendocrine axes controlling anterior and posterior pituitary secretion suggest that most neuroendocrine axes are relatively resilient to CVS. [ABSTRACT FROM AUTHOR]

Migration is an effective behavioral strategy for prolonging access to seasonal resources and may be a resilient strategy for ungulates experiencing changing climatic conditions. In the Greater Yellowstone Ecosystem (GYE), elk are the primary ungulate, with approximately 20,000 individuals migrating to exploit seasonal gradients in forage while also avoiding energetically costly snow conditions. How climate‐induced changes in plant phenology and snow accumulation are influencing elk migration timing is unknown. We present the most complete record of elk migration across the GYE, spanning 9 herds and 414 individuals from 2001 to 2017, to evaluate the drivers of migration timing and test for temporal shifts. The timing of elk departure from winter range involved a trade‐off between current and anticipated forage conditions, while snow melt governed summer range arrival date. Timing of elk departure from summer range and arrival on winter range were both influenced by snow accumulation and exposure to hunting. At the GYE scale, spring and fall migration timing changed through time, most notably with winter range arrival dates becoming almost 50 days later since 2001. Predicted herd‐level changes in migration timing largely agreed with observed GYE‐wide changes—except for predicted winter range arrival dates which did not reflect the magnitude of change detected in the elk telemetry data. Snow melt, snow accumulation, and spring green‐up dates all changed through time, with different herds experiencing different rates and directions of change. We conclude that elk migration is plastic, is a direct response to environmental cues, and that these environmental cues are not changing in a consistent manner across the GYE. The impacts of changing elk migration timing on predator–prey dynamics, carnivore–livestock conflict, disease ecology, and harvest management across the GYE are likely to be significant and complex. [ABSTRACT FROM AUTHOR]

Background and Aim Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations ( HFE wild types) as comparison groups. Methods A sample of the Melbourne Collaborative Cohort Study was selected for the 'HealthIron' study ( n = 1438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing. Results For p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), P < 0.001) during the first 10 years postmenopause, after which SF continued to increase but at less than half the previous rate. In contrast, SF profiles for other HFE genotype groups increase more gradually and did not show a distinction between premenopausal and postmenopausal SF levels. Only p.C282Y homozygotes had predicted SF exceeding 200 μg/L postmenopause, but the projected SF did not increase the risk of iron overload-related disease. Conclusions These data provide the first documented evidence that physiological blood loss is a major factor in determining the marked gender difference in expression of p.C282Y homozygosity. [ABSTRACT FROM AUTHOR]

ABSTRACT Fibronectin (FN) is a widely expressed molecule that can participate in development of osteoarthritis (OA) affecting cartilage, meniscus, and synovial membrane (SM). The alternatively spliced isoforms of FN in joint tissues other than cartilage have not been extensively studied previously. The present study compares FN splice variation in patients with varying degrees of osteoarthritic change. Joint tissues were collected from asymptomatic donors and patients undergoing arthroscopic procedures. Total RNA was amplified by PCR using primers flanking alternatively spliced Extra Domain A (EDA), Extra Domain B (EDB) and Variable (V) regions. EDB+, EDB− and EDA− and V+ variants were present in all joint tissues, while the EDA+ variant was rarely detected. Expression levels of EDB+ and EDV+ variants were similar in cartilage, synovium, and meniscal tissues. Synovial expression of V+ FN in arthroscopy patients varied with degree of cartilage degeneration. Two V− isoforms, previously identified in cartilage, were also present in SM and meniscus. Fibronectin splicing in meniscus and SM bears striking resemblance to that of cartilage. Expression levels of synovial V+ FN varied with degree of cartilage degeneration. V+ FN should be investigated as a potential biomarker of disease stage or progression in larger populations. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:556-562, 2015. [ABSTRACT FROM AUTHOR]

The ferritin core is composed of fine nanoparticulate Fe3+ oxohydroxide, and we have developed a synthetic mimetic, nanoparticulate Fe3+ poly-oxohydroxide (nanoFe3+). The aim of this study was to determine how dietary iron derived in this fashion is absorbed in the duodenum. Following a 4 wk run-in on an Fe-deficient diet, mice with intestinal-specific disruption of the Fpn-1 gene (Fpn-KO), or littermate wild-type (WT) controls, were supplemented with Fe2+ sulfate (FeSO4), nanoFe3+, or no added Fe for a further 4 wk. A control group was Fe sufficient throughout. Direct intestinal absorption of nanoFe3+ was investigated using isolated duodenal loops. Our data show that FeSO4 and nanoFe3+ are equally bioavailable in WT mice, and at wk 8 the mean ± SEM hemoglobin increase was 18 ± 7 g/L in the FeSO4 group and 30 ± 5 g/L in the nanoFe3+ group. Oral iron failed to be utilized by Fpn-KO mice and was retained in enterocytes, irrespective of the iron source. In summary, although nanoFe3+ is taken up directly by the duodenum its homeostasis is under the normal regulatory control of dietary iron absorption, namely via ferroportin-dependent efflux from enterocytes, and thus offers potential as a novel oral iron supplement. [ABSTRACT FROM AUTHOR]

ABSTRACT RFamide-related peptide-3 (RFRP-3) neurons have been shown to inhibit gonadotropin-releasing hormone (GnRH) neuronal activity and hence reproduction in birds and eutherian mammals. They have also been proposed to have a direct hypophysiotropic effect on pituitary gonadotropin release. We used a new RFRP-3 antibody to characterize the cell body distribution and fiber projections of RFRP-3 neurons in the adult female brushtail possum brain. RFRP-3-immunoreactive cell bodies were found scattered within the dorsomedial hypothalamus and the dorsomedial half of the ventromedial hypothalamus, while GnRH neurons were observed scattered rostrocaudally along the lateral septum, rostral to the medial septum. There was a significant 2-fold increase in the RFRP-3 cell body number during the nonbreeding season (summer) compared to the breeding season (winter). Immunoreactive RFRP-3 fibers were distributed throughout the thalamus, preoptic area, and hypothalamus. Very few fibers were observed in the median eminence, especially in the external zone. Intraperitoneal injection of the retrograde tracer Fluoro-Gold resulted in the labeling of 40% of hypophysiotropic tuberoinfundibular dopaminergic (tyrosine hydroxylase-positive) neurons; however, <10% of zona incerta dopaminergic neurons (which are not hypophysiotropic) or RFRP-3 neurons were labeled with this tracer. These observations suggest that RFRP-3 exhibits a seasonal fluctuation in cell numbers, as seen in sheep and birds, which is consistent with an increased inhibitory tone during the nonbreeding season. The lack of RFRP-3 fibers in the median eminence and of Fluoro-Gold uptake from the periphery imply that the actions of this peptide occur primarily centrally rather than at the anterior pituitary gland. J. Comp. Neurol. 521: 3030-3041, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

During pregnancy, neuroendocrine control of prolactin secretion is markedly altered to allow a state of hyperprolactinaemia to develop. Prolactin secretion is normally tightly regulated by a short-loop negative-feedback mechanism, whereby prolactin stimulates activity of tuberoinfundibular dopamine (TIDA) neurones to increase dopamine secretion into the pituitary portal blood. Dopamine inhibits prolactin secretion, thus reducing prolactin concentrations in the circulation back to the normal low level. Activation of this feedback secretion by placental lactogen during pregnancy maintains relatively low levels of prolactin secretion during early and mid-pregnancy. Despite the continued presence of placental lactogen, however, dopamine secretion from TIDA neurones is reduced during late pregnancy. Moreover, the neurones become completely unresponsive to endogenous or exogenous prolactin at this time, allowing a large nocturnal surge of prolactin to occur from the maternal pituitary gland during the night before parturition. In this review, we describe the changing patterns of prolactin secretion during pregnancy in the rat, and discuss the neuroendocrine mechanisms controlling these changes. The loss of response to prolactin is an important maternal adaptation to pregnancy, allowing the prolonged period of hyperprolactinaemia required for mammary gland development and function and for maternal behaviour immediately after parturition, and possibly also contributing to a range of other adaptive responses in the mother. [ABSTRACT FROM AUTHOR]