Direct Feedback Mechanism Research Articles

Abstract MP17: Angiotensin II Inhibits Renin Secretion Directly By Eliciting Robust Calcium Oscillations In Juxtaglomerular Cells

Background: Renin secretion from the juxtaglomerular (JG) cells controls circulating Angiotensin II (AngII), a critical blood pressure determinant. AngII is believed to suppress renin release from JG cells to prevent excessive blood pressure elevation. However, a direct negative feedback mechanism has yet to be established in JG cells. In JG cells, Ca 2+ is a crucial second messenger that governs renin secretion by suppressing cAMP, a potent renin secretion stimulator. Thus, in contrast to most secretory cells, renin secretion from JG cells is inversely related to the intracellular Ca 2+ level. However, the role of AngII in modulating JG cell Ca 2+ dynamics remains unclear. Objective: Define intracellular Ca 2+ responses to AngII and identify the critical channels to suppress renin secretion in JG cells. Methods: Kidney slices from mice expressing JG-specific GCaMP6f, a genetically encoded Ca 2+ indicator under the control of the Ren1 c promoter, were imaged ex vivo on a widefield fluorescent microscope for 30 min per experiment (n = 5). In each experiment, slices were continuously perfused with buffer containing variable Ca 2+ and AngII concentrations, ± specific Ca 2+ channel inhibitors. Images were captured at 10 Hz and analyzed using Mesmerize Ca 2+ imaging software to identify and plot fluorescent intensity over time for each JG cell. Additional kidney slices were incubated in 24-well plates with buffer containing vehicle or AngII ± Ca 2+ channel inhibitors for 30 min. ELISA determined renin concentration. Results: 1) AngII dose-dependently evoked robust and periodic Ca 2+ -oscillations (Ca 2+ spikes) in JG cells (mean spikes/min; 50 pM: 5.4, 300 pM: 7.7, 3 nM: 13.2, and 300 nM: 17.6). 2) AngII-elicited Ca 2+ activity was markedly reduced with “Ca 2+ -free” buffer. 3) L-type voltage-dependent Ca 2+ channel (VDCC) blocker nifedipine moderately decreased AngII-elicited Ca 2+ spikes, while T-type VDCC blocker TTA-P2 did not. 4) Blocking endoplasmic reticulum (ER) Ca 2+ -release drastically reduced Ca 2+ activity. 5) AngII dose-dependently decreased renin secretion in kidney slices, congruent with the AngII-elicited Ca 2+ activity in imaging studies. Conclusion: AngII dose-dependently and directly elicited large, periodic Ca 2+ -oscillations in JG cells that suppressed renin release. Both extracellular Ca 2+ influx and intracellular Ca 2+ release from ER stores are required for sustained Ca 2+ activity. L-type, but not T-type, Ca 2+ channels participate in JG cell Ca 2+ -oscillations.

Transcription coordinates histone amounts and genome content

Biochemical reactions typically depend on the concentrations of the molecules involved, and cell survival therefore critically depends on the concentration of proteins. To maintain constant protein concentrations during cell growth, global mRNA and protein synthesis rates are tightly linked to cell volume. While such regulation is appropriate for most proteins, certain cellular structures do not scale with cell volume. The most striking example of this is the genomic DNA, which doubles during the cell cycle and increases with ploidy, but is independent of cell volume. Here, we show that the amount of histone proteins is coupled to the DNA content, even though mRNA and protein synthesis globally increase with cell volume. As a consequence, and in contrast to the global trend, histone concentrations decrease with cell volume but increase with ploidy. We find that this distinct coordination of histone homeostasis and genome content is already achieved at the transcript level, and is an intrinsic property of histone promoters that does not require direct feedback mechanisms. Mathematical modeling and histone promoter truncations reveal a simple and generalizable mechanism to control the cell volume- and ploidy-dependence of a given gene through the balance of the initiation and elongation rates.

Twitter made me do it! Twitter's tonal platform incentive and its effect on online campaigning

ABSTRACT Does Twitter trigger negative tones in politicians' digital communication? On social media direct feedback mechanisms such as retweets or likes signal to politicians which message and tone are popular. Current research suggests that negative language increases the number of retweets a single tweet receives, indicating preferences for negativity in the audience on Twitter. However, it remains unclear whether politicians adapt to the logic of Twitter or simply follow the rules determined by the broader political context, namely the state of their electoral race. We use sentiment analysis to measure the tone used by 342 candidates in 97,909 tweets in their Twitter campaign in the 2018 midterm elections for the US House of Representatives and map the ideological composition of each politician's Twitter network. We show that the feedback candidates receive creates an incentive to use negativity. The size and direction of the tonal incentive is connected to the ideological composition of the candidate's follower network. Unexpectedly, the platform-specific incentive does not affect the tone used by candidates in their Twitter campaigns. Instead we find that the tone is mainly related to characteristics of the electoral race. We show that our findings are not dependent on our sentiment measurement by validating our results using hand coding and machine learning.

Sustainable feedstocks selection and renewable products allocation: A new hybrid adaptive utility-based consensus model

Nowadays, preferred compromise response of renewable energies' demands regarding the candidate sustainable feedstocks is a crucial issue for market change management. Thus, selecting the most suitable sustainable feedstock is a key factor for optimum renewable products allocation problem. To address the issue, this study proposes a hybrid adaptive framework based on consensus evaluation approach, weighting and ranking procedure, and preferred demand assignment under dynamic hesitant fuzzy sets. In this respect, the consensus evaluation approach is tailored regarding the direct and indirect feedback mechanisms to enhance the quality evaluation of candidate sustainable feedstocks under assessment criteria. Thereby, the weight of each criterion is determined based on the developed dynamic hesitant fuzzy entropy method and the candidate sustainable feedstocks are ranked with respect to developed dynamic hesitant fuzzy positive and negative ideal solutions. Then, a revised multi-choice goal programming model is extended regarding the dynamic hesitant fuzzy closeness indexes to attend to preferred compromise response of demand centers by optimum renewable products allocation. Meanwhile, the presented hybrid adaptive framework is implemented to a real case study to represent the applicability and efficiency of the proposed approach. Furthermore, a comparative analysis is provided by defining eight comparison indexes to compare the obtained results with two recent studies in relevant literature for representing the validation and verification of the proposed approach. The comparative analysis shows that the proposed approach versus the two other approaches has merits such as modeling of uncertainty, experts' weights, adaptive structure, unanimous agreement-based approach, and last aggregation framework. Finally, a sensitivity analysis is represented to show the sensitiveness and robustness of the obtained results from changing the criteria weights, goals values, and consensus elimination. Thereby, the sensitivity analysis indicates that the obtained ranking results are sensitive to sustainability criteria unlike the technical criterion.

Transition Period of the Dairy Cow Revisited: I. Homeorhesis and Its Changes by Selection and Management

The transition period of the dairy cow involves the end of pregnancy, parturition, and the onset of lactation. Multifaceted and rapid changes occur during this time, and in particular, the increase of milk secretion requires the large-scale reorientation of metabolism. The underlying mechanisms of this metabolic regulation are collectively named homeorhesis, a process that governs milk production during this phase and that exhibits (A) a chronic nature, (B) the simultaneous inclusion of multiple tissues, and (C) altered responses to homeostatic signals, but (D) no direct feedback mechanisms for possible control or limitation. Priority of milk production is one important consequence of this homeorhetic regulation with possible constraints on other physiological functions. These general properties of the homeorhetic regulation of milk secretion are specifically characterized by a) milk production according milking (suckling) frequency, b) a natural but inadequate dry matter intake, c) the mobilization of fat acids + glycerol from adipose tissue and of amino acids from protein, d) the partitioning of metabolites, IgG, and dietary nutrients to the mammary gland, e) the stimulation of milk production by high protein intake, and f) a negligible negative energy balance (NEB) at low milk production. Such a combination assures the optimal milk yield for the nutrition of the calf and for its successful survival but without a metabolic challenge or health risk for the cow. However, selection for higher milk production (uncoupled from calf nutrition) and management have changed the above-listed properties, and the regulation of homeorhetic milk production of the modern high-producing dairy cow is nowadays mostly characterized by a) increasing and maximal milk production at increased milking frequency and, under certain circumstances, the uncoupling of the GH-IGF-1 axis, b) enduring insufficient dry matter intake in relation to requirement, c) the mobilization of energy (lipolysis) and release of non-esterified fatty acids (NEFA) above the acute requirement, d) the mobilization of amino acids, e) the partitioning of metabolites, IgG, and dietary nutrient to the mammary gland, f) the potential enhanced partitioning of energy to the mammary gland at high CP intake, g) a sudden and long-lasting NEB, and h) possibly lower weight gain or even net loss of energy during the entire lactation period. These altered and often unfavorable characteristics of high milk production are, furthermore, still regulated by homeorhesis and are thus also given top priority, lack feedback control, and possibly ensue at the expense of other functions without regard for health risks. Hence, the promotion of milk yield by breeding or management might cause metabolic overload, imbalances, or even antagonisms and makes possible health hazards evident. The high incidence of various diseases, the untimely culling rates, and the increasing number of dead cows during early lactation support the assumption of general health threats at high milk production. For this reason, more attention should be paid to the physiological mechanisms of homeorhetic-regulated milk production, its indisputable alterations by breeding and management, and the resulting health risks.

Reducing Interruptive Alert Burden Using Quality Improvement Methodology.

Increased adoption of electronic health records (EHR) with integrated clinical decision support (CDS) systems has reduced some sources of error but has led to unintended consequences including alert fatigue. The "pop-up" or interruptive alert is often employed as it requires providers to acknowledge receipt of an alert by taking an action despite the potential negative effects of workflow interruption. We noted a persistent upward trend of interruptive alerts at our institution and increasing requests for new interruptive alerts. Using Institute for Healthcare Improvement (IHI) quality improvement (QI) methodology, the primary objective was to reduce the total volume of interruptive alerts received by providers. We created an interactive dashboard for baseline alert data and to monitor frequency and outcomes of alerts as well as to prioritize interventions. A key driver diagram was developed with a specific aim to decrease the number of interruptive alerts from a baseline of 7,250 to 4,700 per week (35%) over 6 months. Interventions focused on the following key drivers: appropriate alert display within workflow, clear alert content, alert governance and standardization, user feedback regarding overrides, and respect for user knowledge. A total of 25 unique alerts accounted for 90% of the total interruptive alert volume. By focusing on these 25 alerts, we reduced interruptive alerts from 7,250 to 4,400 per week. Systematic and structured improvements to interruptive alerts can lead to overall reduced interruptive alert burden. Using QI methods to prioritize our interventions allowed us to maximize our impact. Further evaluation should be done on the effects of reduced interruptive alerts on patient care outcomes, usability heuristics on cognitive burden, and direct feedback mechanisms on alert utility.

Tumor-derived microvesicles mediate human breast cancer invasion through differentially glycosylated EMMPRIN.

Tumor cells secrete not only a variety of soluble factors, but also extracellular vesicles that are known to support the establishment of a favorable tumor niche by influencing the surrounding stroma cells. Here we show that tumor-derived microvesicles (T-MV) also directly influence the tumor cells by enhancing their invasion in a both autologous and heterologous manner. Neither the respective vesicle-free supernatant nor MV from benign mammary cells mediate invasion. Uptake of T-MV is essential for the proinvasive effect. We further identify the highly glycosylated form of the extracellular matrix metalloproteinase inducer (EMMPRIN) as a marker for proinvasive MV. EMMPRIN is also present at high levels on MV from metastatic breast cancer patients in vivo. Anti-EMMPRIN strategies, such as MV deglycosylation, gene knockdown, and specific blocking peptides, inhibit MV-induced invasion. Interestingly, the effect of EMMPRIN-bearing MV is not mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway in the tumor cells. In conclusion, T-MV stimulate cancer cell invasion via a direct feedback mechanism dependent on highly glycosylated EMMPRIN.

Biology of childhood germ cell tumours, focussing on the significance of microRNAs.

Genomic and protein-coding transcriptomic data have suggested that germ cell tumours (GCTs) of childhood are biologically distinct from those of adulthood. Global messenger RNA profiles segregate malignant GCTs primarily by histology, but then also by age, with numerous transcripts showing age-related differential expression. Such differences are likely to account for the heterogeneous clinico-pathological behaviour of paediatric and adult malignant GCTs. In contrast, as global microRNA signatures of human tumours reflect their developmental lineage, we hypothesized that microRNA profiles would identify common biological abnormalities in all malignant GCTs owing to their presumed shared origin from primordial germ cells. MicroRNAs are short, non-protein-coding RNAs that regulate gene expression via translational repression and/or mRNA degradation. We showed that all malignant GCTs over-express the miR-371–373 and miR-302/367 clusters, regardless of patient age, histological subtype or anatomical tumour site. Furthermore, bioinformatic approaches and subsequent Gene Ontology analysis revealed that these two over-expressed microRNAs clusters co-ordinately down-regulated genes involved in biologically significant pathways in malignant GCTs. The translational potential of this finding has been demonstrated with the detection of elevated serum levels of miR-371–373 and miR-302/367 microRNAs at the time of malignant GCT diagnosis, with levels falling after treatment. The tumour-suppressor let-7 microRNA family has also been shown to be universally down-regulated in malignant GCTs, because of abundant expression of the regulatory gene LIN28. Low let-7 levels resulted in up-regulation of oncogenes including MYCN, AURKB and LIN28 itself, the latter through a direct feedback mechanism. Targeting LIN28, or restoring let-7 levels, both led to effective inhibition of this pathway. In summary, paediatric malignant GCTs show biological differences from their adult counterparts at a genomic and protein-coding transcriptome level, whereas they both display very similar microRNA expression profiles. These similarities and differences may be exploited for diagnostic and/or therapeutic purposes.

TOWARDS COMPUTATION WITH MICROCHEMOMECHANICAL SYSTEMS

Labs-on-chips are promising candidates for the realization of chemical information systems, where data are embodied in the form of chemical concentrations. In this paper we present the concept of microchemomechanical systems, a lab-on-a-chip technology based on intrinsically active components. The active components are chemical transistors fabricated from phase-changeable polymers that provide a direct feedback mechanism. Therefore this microfluidic platform facilitates the realization of logic operations, if-then structures and the sampling of chemical signals. In analogy with electronic von Neumann CPUs, control and execution unit are integrated on a single chip. Due to the intrinsic activity of the chemical transistors and their small size, microchemomechanical systems are highly suitable for large-scale integration.

New Nebulizer Technology to Monitor Adherence and Nebulizer Performance in Cystic Fibrosis

Topical delivery of aerosolized therapies is an established treatment for chronic airway infection and inflammation in cystic fibrosis (CF). Recent developments in nebuliser technology have enabled Adaptive Aerosol Delivery (AAD) of mesh generated aerosol particles resulting in more efficient airway deposition than existing jet nebulizers. An additional feature of these new devices is the ability to record and examine the performance of the device by downloading stored data (electronic data capture). In a series of studies we have used this downloading facility to monitor treatment times and examine adherence to nebulizer therapy in our pediatric patients. We found routine adherence monitoring is possible in busy CF clinic. We have shown that good adherence to treatment can be maintained in both patients chronically infected with Pseudomonas aeruginosa on long-term therapy, and in patients with first/new growths of Pseudomonas on short-term eradication therapy. When adherence was examined from an individual perspective, we demonstrated a wide variation both between and within individual patients. A further modification of AAD technology, Target Inhalation Mode (TIM) optimises patient inhalations through a direct feedback mechanism. This new breathing mode has also been evaluated in our pediatric CF clinic in a recent randomized controlled trial (RCT) and we have shown that children maintain adherence to treatment through the TIM mouthpiece and average treatment times reduced from 6.9 to 3.7 min when using TIM. This is a new era of aerosol delivery and novel advances in medical devices need to be monitored and assessed rigorously, particularly as new and potentially expensive therapies emerge from translational studies. Electronic data capture enables CF teams to work in an open partnership with patients to achieve the common goals of improving drug delivery and reducing patient burden.

Distributed Democracy: SeeClickFix.Com for Crowdsourced Issue Reporting

This document explores one case of the growing Government 2.0 eco-system in the United States of America. SeeClickFix.com (SCF) is a web-based service designed to help citizens report non-emergency issues in their neighborhood. The submissions can be submitted via a web interface, by iPhone, Blackberry and Android reporting apps and a Facebook application. Local government officials receive alerts about submitted issues or can track issues that citizens submitted via the so-called 'Watch Area' they are responsible for. The platform allows for direct feedback mechanisms: Local government officials assign a work order number and can change the status of the repair (from open, in progress, to fixed). Citizens are automatically informed about changes in the status of their reported issues allowing for a full feedback cycle. The service is integrated into the social networking services Twitter and Facebook and provides map-based reporting widgets for government and newspaper websites.

A randomised controlled trial of breathing modes for adaptive aerosol delivery in children with cystic fibrosis

Background Aerosol delivery is a cornerstone of CF airways disease management. New nebulisers have reduced treatment times by utilising mesh technology for aerosol production. We have evaluated a further modification (target inhalation mode (TIM)) that may reduce treatment delivery times further. Methods Following a baseline period on tidal breathing mode (TBM), children with CF on long-term aerosol therapy were randomly allocated to either TIM, which optimises patient inhalations through a direct feedback mechanism, or to continue TBM. The primary outcome was nebuliser treatment times with secondary outcomes being adherence and patient preference. Results The ten children allocated TIM reduced their mean (SD) treatment times from 6.9(2.9) to 3.7(2.3) minutes (p < 0.001). In contrast, treatment times were unchanged in the ten children allocated TBM. Mean adherence was maintained in the TIM group but declined in patients allocated TBM by > 5%. All children preferred TIM to TBM. Conclusion TIM reduces nebuliser treatment times and may positively impact on adherence, although longer duration studies are required to examine this. (ISRCTN65617839)

The links between international parity conditions and Granger causality: a study of exchange rates and prices

This article investigates Granger causality between exchange rates and prices for the US and four of its trading partners: Canada, Germany, Japan and the UK. We emphasize the distinction between direct and indirect Granger causality: exchange rates directly cause prices if movements in exchange rates lead movement in prices, and exchange rates indirectly cause prices if deviations from the Purchasing Power Parity (PPP) condition can help forecast movement in prices. But only by including the interest-rate differential in our error correction model do we obtain results that align with economic theory. The economic theory of PPP suggests that exchange rates and prices are cointegrated, with exchange rates moving proportionally to prices in the long run. In general, we find either direct or indirect feedback mechanisms between exchange rates and prices.

Leptin concentrations and the immune-mediated reduction of feed intake in sheep infected with the nematode Trichostrongylus colubriformis

The hypothesis that increases in the concentration of the anorectic peptide leptin may be responsible for the immune-mediated reduction in feed intake (FI) during gastrointestinal parasitism in sheep was investigated. In a 2 x 2 x 2 factorial design, the first factor was age at the start of infection (5 months old v. 17 months old). The second factor was parasite infection (no infection v. administration of eighty L3 infective Trichostrongylus colubriformis larvae/kg live weight (LW) per d three times per week for 77 d). The third factor was immunosuppressive therapy with a corticosteroid (no therapy or weekly intramuscular injection of 40 mg methylprednisolone acetate/30 kg LW). Relative to their uninfected counterparts, a 20 % reduction in FI per unit LW (FI/LW; g DM/kg LW) was observed in infected non-suppressed 5-month-old lambs from 21 to 63 d post-infection (P < 0.001) but not in comparable17-month-old ewes or in corticosteroid-treated lambs or ewes (P>0.05 for all), allowing the suggestion that the anorexia was a consequence of the developing immune response. The reduction in FI/LW in 5-month-old lambs was not associated with an increase in plasma leptin concentration. Furthermore, plasma leptin concentrations were greater in corticosteroid-treated animals (P < 0.001) and in 17-month-old animals (P < 0.001), none of which displayed an infection-induced reduction in FI/LW. Plasma leptin was positively correlated with carcass fat percentage in both 5-month-old (P = 0.016) and 17-month-old (P < 0.001) animals and did not appear to provide a direct feedback mechanism that restricted energy intake. The results do not support the hypothesis that an increase in circulating leptin is directly responsible for the immune-mediated anorexia in lambs during T. colubriformis infection.

P19ARF directly and differentially controls the functions of c-Myc independently of p53.

Increased expression of the oncogenic transcription factor c-Myc causes unregulated cell cycle progression. c-Myc can also cause apoptosis, but it is not known whether the activation and/or repression of c-Myc target genes mediates these diverse functions of c-Myc. Because unchecked cell cycle progression leads to hyperproliferation and tumorigenesis, it is essential for tumour suppressors, such as p53 and p19ARF (ARF), to curb cell cycle progression in response to increased c-Myc (refs 2, 3). Increased c-Myc has previously been shown to induce ARF expression, which leads to cell cycle arrest or apoptosis through the activation of p53 (ref. 4). Here we show that ARF can inhibit c-Myc by a unique and direct mechanism that is independent of p53. When c-Myc increases, ARF binds with c-Myc and dramatically blocks c-Myc's ability to activate transcription and induce hyperproliferation and transformation. In contrast, c-Myc's ability to repress transcription is unaffected by ARF and c-Myc-mediated apoptosis is enhanced. These differential effects of ARF on c-Myc function suggest that separate molecular mechanisms mediate c-Myc-induced hyperproliferation and apoptosis. This direct feedback mechanism represents a p53-independent checkpoint to prevent c-Myc-mediated tumorigenesis.

Intercellular communication between renin expressing As4.1 cells, endothelial cells and smooth muscle cells

Angiotensin II (AII) regulation of renin production by the juxtaglomerular (JG) cells of the kidney is commonly thought to occur through a direct feedback mechanism. However, recent evidence suggests that other cells in the vicinity may indirectly mediate AII's effect on renin production. Therefore we investigated whether an in vitro model of JG cells (As4.1) could have intercellular communication with endothelial or smooth muscle cells, which are in proximity to JG cells in vivo. 6-carboxyfluorescein was introduced to individual bovine aortic endothelial cells in co-culture with As4.1 cells. Coupling was observed 84% of the time at resting membrane potential and was attenuated by membrane depolarization or octanol (1 mM). Calcein green transfer between human aortic smooth muscle and As4.1 cells occurred 82% of the time and was inhibited by octanol. Expression of connexin 37, 40, 43, and 45 were detected in As4.1 cells using RT-PCR. Stimulation of As4.1 cells by AII failed to alter [Ca 2+] i or renin mRNA levels. These findings support the existence of gap junctions between renin producing cells and other cell types of the JG region. Moreover the lack of effect by AII suggest that feedback regulation of renin by AII may be due in part to intercellular communication with cells in proximity to JG cells.

Attractable snakes based on the greedy algorithm for contour extraction

While most improved snakes were built under the original variational scheme, this paper presents an attractable snake based on the greedy snake (Williams and Shah, CVGIP: Image Understanding 55(1) (1992) 14–26). By use of a direct feedback mechanism that is seamlessly consistent with the search strategy of the greedy algorithm, the proposed approach is capable of inheriting the simplicity and efficiency of that algorithm and performing competitively with related snakes. To avoid undesirable local minima, an overall optimal edge detector is designed. A suitable synthetic convergent criterion is proposed which enables snakes to converge normally or oscillatingly on target objects. An adaptive interpolation scheme that encourages snakes to accurately sense the details of object shapes is also described. This model is applied to extract contours from various images with encouraging results.

Inhibition of IL-12 production in human monocyte-derived macrophages by TNF.

IL-12 is a pivotal cytokine that links the innate and adaptive immune responses. TNF-alpha also plays a key role in orchestrating inflammation and immunity. The reciprocal influence of these two inflammatory mediators on each other may have significant impact on the cytokine balance that shapes the type and extent of immune responses. To investigate the relationship between TNF-alpha and IL-12 production, we analyzed the effects of exposure of human monocyte-derived macrophages to TNF-alpha on LPS- or Staphylococcus aureus-induced IL-12 production in the presence or absence of IFN-gamma. TNF-alpha is a potent inhibitor of IL-12 p40 and p70 secretion from human macrophages induced by LPS or S. aureus. IL-10 is not responsible for the TNF-alpha-mediated inhibition of IL-12. TNF-alpha selectively inhibits IL-12 p40 steady-state mRNA, but not those of IL-12 p35, IL-1alpha, IL-1beta, or IL-6. Nuclear run-on analysis identified this specific inhibitory effect at the transcriptional level for IL-12 p40 without down-regulation of the IL-12 p35 gene. The major transcriptional factors identified to be involved in the regulation of IL-12 p40 gene expression by LPS and IFN-gamma, i.e., c-Rel, NF-kappaB p50 and p65, IFN regulatory factor-1, and ets-2, were not affected by TNF-alpha when examined by nuclear translocation and DNA binding. These data demonstrate a selective negative regulation on IL-12 by TNF-alpha, identifying a direct negative feedback mechanism for inflammation-induced suppression of IL-12 gene expression.

A new capability: postpublication peer review for pediatrics

Beginning with this month's issue of Pediatrics , we will introduce a new and potentially transformational capability for the journal via its on-line version. We are calling this feature “Postpublication Peer Review,” or P3R. Traditional peer review is conducted by one or more (preferably two or more) respected peers during a prepublication screening process. For Pediatrics , this process eliminates nearly 80% of the manuscripts submitted to the journal in any given year. Once a study is published, however, a slow and rather cumbersome method of subsequent review, via Letters to the Editor, has been the only direct feedback mechanism available to authors, with subsequent studies being the other, even … Address correspondence to Kent R. Anderson, Director, Division of Medical Journals and Professional Periodicals, American Academy of Pediatrics, 141 Northwest Point Blvd, Elk Grove Village, IL 60007-1098.

Regulation by estradiol of the progesterone receptor in the hypothalamus and pituitary: an immunohistochemical study in the chicken.

An antibody (IgG-RB) against the chick oviduct progesterone receptor (PR) was used to study the regulation of PR by estrogen in chicken pituitary and hypothalamus. PR was revealed exclusively in cell nuclei, whatever the hormonal state, including the absence of progesterone. In immature untreated chickens, PR was not detected in the pars distalis, while the pars tuberalis, preoptic area, and infundibular region of hypothalamus showed IgG-RB-immunoreactive cells or neurons. Estrogenic stimulation induced the appearance of PR in cells of the pars distalis and increased the immunoreactivity in the hypothalamus of young chickens of both sexes. After hormonal withdrawal, PR immunostaining returned to the level in untreated immature animals. In young hens, before they laid the first egg, PR appears progressively in pars distalis cells during the pubertal period. Antibodies to pituitary hormones (LH, FSH, GH, PRL, and ACTH) were used to characterize the secretory properties of PR-containing cells. LH- and FSH-immunoreactive cells were localized throughout the pars distalis in untreated animals. After estradiol treatment of young sexually immature chickens, immunostaining of LH and FSH was strongly reduced, up to extinction, in many gonadotropic cells, and only few PR-containing cells demonstrated some immunoreactivity in the cytoplasm. In contrast, in juvenile hens, a majority of PR-containing cells were identified as LH immunoreactive, that is gonadotrophs. There are probably two reasons for the paucity of doubly reactive cells in estradiol-treated chickens. One is technical, the optimal fixation time for both LH (greater than 20 h) and PR (less than 7 h) makes it practically impossible to reveal the hormone and the receptor at the same time. The other is related to the physiology of the system, which involves the simultaneous decrease in LH immunoreactivity and the PR induction in gonadotrophs by estradiol. The presence of PR in gonadotrophs suggests a direct feedback mechanism of sex steroids on pituitary cells in addition to the indirect effect through GnRH modulation. The hormonal content of PRL-, GH-, and ACTH-producing cells was not modified by estradiol treatment, as judged by the appropriate immunoreactivity, and their nuclei did not display PR. However, PRL cells and PR-containing cells were frequently present near each other within the same cell cords.