bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucocorticoids as Entraining Signals for Peripheral Circadian Oscillators
Authors: Pezük Pınar , Mohawk Jennifer A. , Wang Laura A. , Menaker Michael 
Published: September 2012

Abstract
Mammalian circadian organization is governed by pacemaker neurons in the brain that communicate with oscillators in peripheral tissues. Adrenal glucocorticoids are important time-giving signals to peripheral circadian oscillators. We investigated the rhythm of Per1-luc expression in pineal, pituitary, salivary glands, liver, lung, kidney, cornea as well as suprachiasmatic nucleus from adrenalectomized and sham-operated rats kept under light-dark cycles, or exposed to single 6-h phase delays or advances of their light cycles. Adrenalectomy shifted the phases of Per1-luc in liver, kidney, and cornea and caused phase desynchrony and significant dampening in the rhythmicity of cornea. Treatment with hydrocortisone shifted the phases of Per1-luc in most of the tissues examined, even those that were not affected by adrenalectomy. The rhythm in cornea recovered in animals given hydrocortisone in vivo or when corneas were treated with dexamethasone in vitro. Adrenalectomy increased the rate of reentrainment after phase shifts in liver, kidney, cornea, pineal, lung, and suprachiasmatic nucleus but not in pituitary and salivary glands. Our data show that glucocorticoids act as strong entraining signals for peripheral circadian oscillators and may feed back on central oscillators as well.
Estradiol Partially Recapitulates Murine Pituitary Cell Cycle Response to Pregnancy
Authors: Toledano Yoel , Zonis Svetlana , Ren Song-Guang , Wawrowsky Kolja , Chesnokova Vera , Melmed Shlomo 
Published: September 2012

AbstractBecause pregnancy and estrogens both induce pituitary lactotroph hyperplasia, we assessed the expression of pituitary cell cycle regulators in two models of murine pituitary hyperplasia. Female mice were assessed during nonpregnancy, pregnancy, day of delivery, and postpartum. We also implanted estradiol (E2) pellets in female mice and studied them for 2.5 months. Pituitary weight in female mice increased 2-fold after E2 administration and 1.4-fold at day of delivery, compared with placebo-treated or nonpregnant females. Pituitary proliferation, as assessed by proliferating cell nuclear antigen and/or Ki-67 staining, increased dramatically during both mid-late pregnancy and E2 administration, and lactotroph hyperplasia was also observed. Pregnancy induced pituitary cell cycle proliferative and inhibitory responses at the G1/S checkpoint. Differential cell cycle regulator expression included cyclin-dependent kinase inhibitors, p21Cip1, p27Kip1, and cyclin D1. Pituitary cell cycle responses to E2 administration partially recapitulated those effects observed at mid-late pregnancy, coincident with elevated circulating mouse E2, including increased expression of proliferating cell nuclear antigen, Ki-67, p15INK4b, and p21Cip1. Nuclear localization of pituitary p21Cip1 was demonstrated at mid-late pregnancy but not during E2 administration, suggesting a cell cycle inhibitory role for p21Cip1 in pregnancy, yet a possible proproliferative role during E2 administration. Most observed cell cycle protein alterations were reversed postpartum. Murine pituitary meets the demand for prolactin during lactation associated with induction of both cell proliferative and inhibitory pathways, mediated, at least partially, by estradiol.
The Thyroid Axis Is Regulated by NCoR1 via Its Actions in the Pituitary
Authors: Costa-e-Sousa Ricardo H. , Astapova Inna , Ye Felix , Wondisford Fredric E. , Hollenberg Anthony N. 
Published: September 2012

AbstractTSH is the most important biomarker in the interpretation of thyroid function in man. Its levels are determined by circulating thyroid hormone (TH) levels that feed back centrally to regulate the expression of the subunits that comprise TSH from the pituitary. The nuclear corepressor 1 (NCoR1), is a critical coregulator of the TH receptor (TR) isoforms. It has been established to play a major role in the control of TSH secretion, because mice that express a mutant NCoR1 allele (NCoRΔID) that cannot interact with the TR have normal TSH levels despite low circulating TH levels. To determine how NCoR1 controls TSH secretion, we first developed a mouse model that allowed for induction of NCoRΔID expression postnatally to rule out a developmental effect of NCoR1. Expression of NCoRΔID postnatally led to a drop in TH levels without a compensatory rise in TSH production, indicating that NCoR1 acutely controls both TH production and feedback regulation of TSH. To demonstrate that this was a cell autonomous function of NCoR1, we expressed NCoRΔID in the pituitary using a Cre driven by the glycoprotein α-subunit promoter (P-ΔID mice). Importantly, P-ΔID mice have low TH levels with decreased TSH production. Additionally, the rise in TSH during hypothyroidism is blunted in P-ΔID mice. Thus, NCoR1 plays a critical role in TH-mediated regulation of TSH in the pituitary by regulating the repressive function of the TR. Furthermore, these studies suggest that endogenous NCoR1 levels in the pituitary could establish the set point of TSH secretion.
A Potential Role of Progestin-Induced Laminin-5/α6-Integrin Signaling in the Formation of Side Branches in the Mammary Gland
Authors: Meyer Gabriele , Leipprandt Jeffrey , Xie Jianwei , Aupperlee Mark D. , Haslam Sandra Z. 
Published: September 2012

AbstractMammary organoids from adult mice produce tubules, analogous to mammary ducts in vivo, in response to hepatocyte growth factor (HGF) when cultured in collagen gels. The combination of HGF plus progestin (R5020) causes reduced tubule number and length. We hypothesized that the inhibitory effect on tubulogenesis was due to progestin-mediated alteration of HGF/c-Met signaling. Using molecular inhibitors and short hairpin RNA, it was determined that HGF activation of Ras-related C3 botulinum toxin substrate (Rac1) was required for the formation of cytoplasmic extensions, the first step of tubulogenesis, and that Rac1 activity was Src kinase (Src) and focal adhesion kinase (FAK) dependent. The highly novel finding was that R5020 reduced tubulogenesis by up-regulating and increasing extracellular laminin and α6-integrin ligation to reduce activation of the Src, focal adhesion kinase, and Rac1 pathway. Receptor activator of nuclear factor-κB ligand, another progesterone-induced paracrine factor, did not replicate this effect of R5020. The inhibitory effect of R5020 on tubulogenesis was likely mediated through progesterone receptor (PR) isoform A (PRA), because PRA is the predominant PR isoform expressed in the organoids, and the progestin-induced effect was prevented by the PR antagonist RU486. These results provide a plausible mechanism that explains progestin/PRA-mediated blunting of HGF-induced tubulogenesis in vitro and is proposed to be relevant to progesterone/PRA-induced side-branching in vivo during pregnancy.
Role of TSH in the Spontaneous Development of Asymmetrical Thyroid Carcinoma in Mice with a Targeted Mutation in a Single Allele of the Thyroid Hormone-β Receptor
Authors: Zhao Li , Zhu Xuguang , Won Park Jeong , Fozzatti Laura , Willingham Mark , Cheng Sheue-yann 
Published: September 2012

AbstractMutations of the thyroid hormone receptor-β gene (THRB) cause resistance to thyroid hormone (RTH). A mouse model of RTH harboring a homozygous thyroid hormone receptor (TR)-β mutation known as PV (ThrbPV/PV mouse) spontaneously develops follicular thyroid cancer (FTC). Similar to RTH patients with mutations of two alleles of the THRB gene, the ThrbPV/PV mouse exhibits elevated thyroid hormones accompanied by highly nonsuppressible TSH. However, the heterozygous ThrbPV/+ mouse with mildly elevated TSH (∼2-fold) does not develop FTC. The present study examined whether the mutation of a single allele of the Thrb gene is sufficient to induce FTC in ThrbPV/+ mice under stimulation by high TSH. ThrbPV/+ mice and wild-type siblings were treated with propylthiouracil (PTU) to elevate serum TSH. ThrbPV/+mice treated with PTU (ThrbPV/+-PTU) spontaneously developed FTC similar to human thyroid cancer, but wild-type siblings treated with PTU did not. Interestingly, approximately 33% of ThrbPV/+-PTU mice developed asymmetrical thyroid tumors, as is frequently observed in human thyroid cancer. Molecular analyses showed activation of the cyclin 1-cyclin-dependent kinase-4-transcription factor E2F1 pathway to increase thyroid tumor cell proliferation of ThrbPV/+-PTU mice. Moreover, via extranuclear signaling, the PV also activated the integrin-Src-focal adhesion kinase-AKT-metalloproteinase pathway to increase migration and invasion of tumor cells. Therefore, mutation of a single allele of the Thrb gene is sufficient to drive the TSH-simulated hyperplastic thyroid follicular cells to undergo carcinogenesis. The present study suggests that the ThrbPV/+-PTU mouse model potentially could be used to gain insights into the molecular basis underlying the association between thyroid cancer and RTH seen in some affected patients.
Antiinflammatory Treatment Ameliorates HPA Stress Axis Dysfunction in a Mouse Model of Stress Sensitivity
Authors: Gerber Alexis R. , Bale Tracy L. 
Published: September 2012

Abstract
Dysregulated stress responsivity is a hallmark of neuropsychiatric disease. The regulation of stress activation and recovery involves tight coordination between neuronal and glial networks. At a certain threshold of sensitivity, stress exposure can evoke a neuroimmune response. Astrocytes are potential mediators of these effects because they are able to respond to neuroimmune effector molecules and regulate neuronal activity. Mice deficient in corticotropin-releasing factor receptor-2 display increased stress sensitivity and are therefore a useful model in which to examine the intersection of neuroimmune activation and stress pathway dysregulation. We hypothesized that a component of elevated stress reactivity may involve an engagement of neuroimmune effectors, including astrocytes. Therefore, we hypothesized that this phenotype may be rescued by concomitant nonsteroidal antiinflammatory drug (NSAID) treatment. To examine this, mice exposed to chronic stress were treated with NSAID in their drinking water, and changes in hypothalamic-pituitary-adrenal stress axis function were examined. As a correlate of altered astrocyte function, levels of glial fibrillary acidic protein were measured. Supportive of our hypothesis, NSAID treatment rescued the hypothalamic-pituitary-adrenal stress axis dysfunction in stress-sensitive corticotropin-releasing factor receptor-2−/− mice and also reversed the stress-induced increase in glial fibrillary acidic protein in stress-regulating brain regions including the paraventricular nucleus of the hypothalamus, ventral hippocampus, and prefrontal cortex. These findings support the local involvement of astrocytes in the exacerbation of stress pathway dysregulation. The specificity of these effects in a stress-sensitive genotype highlights the importance of utilizing a model of stress dysregulation in the examination of factors that may translate to neuropsychiatric disease.
Knockdown of pnpla6 protein results in motor neuron defects in zebrafish
Authors: Song Yang , Wang Molin , Mao Fei , Shao Ming , Zhao Baochang , Song Zhen , Shao Changshun , Gong Yaoqin 
Published: September 2012

SummaryMutations in patatin-like phospholipase domain containing 6 (PNPLA6), also known as neuropathy target esterase (NTE), or SPG39, cause hereditary spastic paraplegia (HSP). Although studies on animal models including mice and Drosophila have extended our understanding of PNPLA6, its role in neural development and HSP is not clearly understood. Here, we generated a vertebrate model of PNPLA6 insufficiency using morpholino oligonucleotide knockdown in zebrafish (Danio rerio). PNPLA6 knockdown results in developmental abnormalities and motor neuron defects including axon truncation and branching. The phenotypes in pnpla6 knockdown morphants can be rescued by introduction of wide type (WT), but not mutant, human PNPLA6 mRNA. Our results also revealed the involvement of BMP signaling in pnpla6 knockdown phenotypes. Taken together, these results demonstrated an important role of PNPLA6 in motor neuron development and implicated overexpression of BMP signaling as the possible mechanism underlying the developmental defects in pnpla6 morphants.
An intronic ncRNA-dependent regulation of SORL1 expression affecting Aβ formation is upregulated in post-mortem Alzheimer's disease brain samples
Authors: Ciarlo Eleonora , Massone Sara , Penna Ilaria , Nizzari Mario , Gigoni Arianna , Dieci Giorgio , Russo Claudio , Florio Tullio , Cancedda Ranieri , Pagano Aldo 
Published: September 2012

Summary
Recent studies indicated sortilin-related receptor 1 (SORL1) to be a risk-gene for late-onset Alzheimer's Disease (AD), although its role in the aetiology and/or progression of this disorder is not fully understood. Here, we report the finding of a novel non-coding (nc) RNA (hereafter referred to as 51A) that maps in antisense (AS) configuration in intron 1 of SORL1 gene. 51A expression drives a splicing shift of SORL1 from the synthesis of the canonical long protein variant 1 to an alternatively spliced protein form. This process, resulting in a decreased synthesis of SORL1 variant 1, is associated with an impaired processing of APP, leading to increase of Aβ formation. Interestingly, we found that 51A is expressed in human brains, being frequently up-regulated in cerebral cortices from Alzheimer's disease patients. Altogether these findings document a novel ncRNA-dependent regulatory pathway that might have relevant implications in neurodegeneration.
An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery
Authors: Willoughby Lee F. , Schlosser Tanja , Manning Samuel A. , Parisot John P. , Street Ian P. , Richardson Helena E. , Humbert Patrick O. , Brumby Anthony M. 
Published: September 2012

Summary
Anti-cancer drug development involves enormous expenditure and risk. Key to the rapid and economic identification of novel, bioavailable anti-tumor chemicals is the use of appropriate in vivo tumor models suitable for large-scale screening. Using a Drosophila Ras-driven tumor model, we demonstrate that tumor overgrowth can be curtailed by feeding larvae chemicals with the in vivo pharmacokinetics essential for drug development and known efficacy against human tumor cells. We then develop an in vivo 96-well plate chemical screening platform to carry out large-scale chemical screening with the tumor model. In a proof-of-principle pilot screen of 2000 compounds we identify the glutamine analog, Acivicin, a chemical with known activity against human tumor cells, as a potent and specific inhibitor of Drosophila tumor formation. RNAi-mediated knockdown of candidate Acivicin target genes implicates an enzyme involved in pyrimidine biosynthesis, CTP synthase, as a possible critical target of Acivicin-mediated inhibition. Thus, the pilot screen has revealed that Drosophila tumors are glutamine-dependent, which is an emerging feature of many human cancers, and has validated the platform as a powerful and economic tool for in vivo chemical screening. The platform can also be adapted for use with other disease models, thus offering wide spread applications in drug development.
Ventilation rates and activity levels of juvenile jumbo squids under metabolic suppression in the oxygen minimum zones
Authors: Trübenbach Katja , Pegado Maria R. , Seibel Brad A. , Rosa Rui 
Published: September 2012

SummaryThe Humboldt (jumbo) squid, Dosidicus gigas, is a part-time resident of the permanent oxygen minimum zone (OMZ) in the Eastern Tropical Pacific and, thereby, it encounters oxygen levels below its critical oxygen partial pressure. To better understand the ventilatory mechanisms that accompany the process of metabolic suppression in these top oceanic predators, we exposed juvenile D. gigas to the oxygen levels found in the OMZ (1% O2, 1kPa, 10ºC) and measured metabolic rates, activity cycling patterns, swimming mode, escape-jet (burst) frequency, mantle contraction frequency and strength, stroke volume and oxygen extraction efficiency. In normoxia, the metabolic rates varied between 14 to 29 µmol O2 g (ww)-1 h-1, depending on the level of activity. The mantle contraction frequency and strength was linearly correlated and increased significantly with activity level. Additionally, an increased stroke volume and ventilatory volume per minute were observed, followed by a mantle hyperinflation process during high activity periods. Squid metabolic rates dropped more than 75% during exposure to hypoxia. Maximum metabolic rates were not achieved under such conditions and the metabolic scope was significantly decreased. Hypoxia changed the relationship between mantle contraction strength and frequency from linear to polynomial with increasing activity indicating that, under hypoxic conditions, the jumbo squid primarily increases the strength of mantle contraction and does not regulate its frequency. Under hypoxia, jumbo squids also showed a larger inflation period (reduced contraction frequency) and decreased relaxed mantle diameters (shortened diffusion pathways), which optimize oxygen extraction efficiency (up to 82%/34%, without/with consideration of 60% potential skin respiration). Additionally, they breathe “deeply”, with more powerful contractions and enhanced stroke volume. This deep-breathing behavior allows them to display a stable ventilatory volume per min, and explains the maintenance of the squid’s cycling activity under such O2 conditions. During hypoxia, the respiratory cycles were shorter in length but increased in frequency. This was accompanied by an increase in the number of escape-jets during active periods and a faster switch between swimming modes. In late hypoxia (onset ~170±10 min), all the ventilatory processes were significantly reduced and followed by a lethargic state, a behavior that seems closely associated with the process of metabolic suppression and enables the squid to extend its residence time in the OMZ.
Associative learning in the dengue vector mosquito,Aedes aegypti: avoidance of a previously attractive odor or surface color that is paired with an aversive stimulus
Authors: Menda Gil , Uhr Joshua H. , Wyttenbach Robert A. , Vermeylen Françoise M. , Smith David M. , Harrington Laura C. , Hoy Ronald R. 
Published: September 2012

SummaryAssociative learning has been shown in a variety of insects, including the mosquitoes Culex quinquefasciatus and Anopheles gambiae. This study demonstrates associative learning for the first time in Aedes aegypti, an important vector of dengue, yellow fever, and chikungunya viruses. This species prefers to rest on dark surfaces and is attracted to the odor of 1-octen-3-ol. After training in which a dark surface alone or a dark surface with odor was paired with electric shock, mosquitoes avoided the previously attractive area. The association was stronger when odor was included in training, was retained for at least 60 min but not for 24 hours, and was equal for males and females. These results demonstrate the utility of a bulk-training paradigm for mosquitoes similar to that used with Drosophila melanogaster.
Tracking bed bugs (Cimex lectularius): a study of the effect of physiological and extrinsic factors on the response to bed bug-derived volatiles
Authors: Weeks Emma N.I. , Logan James G. , Birkett Michael A. , Pickett John A. , Cameron Mary M. 
Published: September 2012

SummaryThe common bed bug, Cimex lectularius, feeds on the blood of mammal and bird hosts, and is a pest of global importance. Semiochemicals are chemicals involved in animal communication that may affect behaviour and/or physiology. Attractive semiochemicals that play a role in mediating bed bug behaviour could be exploited for the development of a highly effective novel monitoring device. Tracking software, was used to record the response of bed bugs to volatiles from paper previously exposed to conspecific bugs in a still-air olfactometer illuminated by infrared lights, through a variety of activity variables. The effect of time of day as an extrinsic factor, and sex, stage, mating status and nutritional status as physiological factors on the response of bed bugs to the volatiles was examined. Bed bugs of both sexes and all stages responded to the volatiles from bed bug-exposed papers, showing significant attraction and orientation towards the volatile source whether they were starved or engorged. Confirmation that the physiological factors examined do not affect the response of bed bugs to the volatiles from bed bug-exposed papers provides evidence that these bed bug derived volatiles contain aggregation cues, as semiochemicals that promote aggregation should by definition be detected by both sexes and all life stages. A device baited with such semiochemicals could play a major role in limiting the impact of the current bed bug resurgence by enabling timely detection of infestations, along with quantitative evaluation of control and effective surveillance of the geographical distribution of the pest species.
Analysis of the transitional flow field over a fixed hummingbird wing
Authors: Elimelech Yossef , Ellington Charles P. 
Published: September 2012

SummaryFlow fields characterized by chord-based Reynolds numbers of 5000 to 15000 over a stationary model of a hummingbird wing (Calypte anna) are analyzed below. Utilizing two experimental techniques, constant-temperature anemometry and particle image velocimetry, the high fidelity results depict a laminar-to-turbulent transition process that develops over the wing. At both zero and non-zero angles of attack the spectrum of the velocity signals is wide. At non-zero angle of attack the flow separates from the wing surface and a shear layer forms. As a result, unsteady flow disturbances amplify at a chord-based Reynolds number which is as low as 5000. Nevertheless, only at a Reynolds number of 15000 is the flow disturbance growth rate sufficient to bring enough momentum to reattach the flow to the wing surface. For a Reynolds number of 5000, a comparison between the observed growth rates to a theoretical approximation concludes that flow disturbances of a Strouhal number of unity (and above) are no longer two-dimensional. In view of these conclusions, this study could serve as the first step toward better understanding of the flow mechanisms over steady revolving and periodically flapping wings at this Reynolds number regime.
Rapid decline of cold tolerance at young age is associated with expression of stress genes in Drosophila melanogaster
Authors: Colinet Hervé , Sciaussat David , Bozzolan Francoise , Bowler Kenneth 
Published: September 2012

Summary
Many endogenous factors influence thermal tolerance of insects. Among these, age contributes an important source of variation. Heat tolerance is typically high in newly-enclosed insects, before declining dramatically. It is not known whether this phenomenon relates to cold tolerance also. In addition, the underlying mechanisms of this variation are unresolved. In this study we tested whether cold tolerance declines in Drosophila melanogaster females aged from 0 to 5 days. We also assessed whether expression (basal and induced) of eight stress genes (hsp22, hsp23, hsp40, hsp68, hsp70Aa, hsp83, Starvin and Frost) varied post-eclosion in correspondence with changes found cold tolerance. We report that cold tolerance was very high at eclosion and then it rapidly declined in young flies. hsp23 and hsp68 showed a dramatic age-related variation of basal expression that was associated with cold tolerance proxies. Significant age-related plasticity of cold-induced expression was also found for hsp22, hsp23, hsp68, hsp70Aa, Frost and Starvin. hsp22 and hsp70Aa induced expression was high in newly-enclosed phenotypes before declining dramatically, whilst opposite age-related patterns were found for hsp23, hsp68, Starvin and Frost. This study shows a marked within-stage variation in cold tolerance. The involvement of the stress genes in setting basal thermal tolerance is discussed.